Glyceraldehyde-3-phosphate dehydrogenase （GAPDH）, initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. H...Glyceraldehyde-3-phosphate dehydrogenase （GAPDH）, initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and pnsttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 （HIF-1）, p53, nitric oxide （NO）, and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications （PTMs） occurring in GAPDH in cancer cells result in new activities unrelated to the original glycnlytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described.展开更多
The development of colorectal cancer(CRC)can be influenced by genetic factors in both familial cases and sporadic cases.Familial CRC has been associated with genetic changes in high-,moderate-and low-penetrance suscep...The development of colorectal cancer(CRC)can be influenced by genetic factors in both familial cases and sporadic cases.Familial CRC has been associated with genetic changes in high-,moderate-and low-penetrance susceptibility genes.However,despite the availability of current gene-identification techniques,the genetic causes of a considerable proportion of hereditary cases remain unknown.Genome-wide association studies of CRC have identified a number of common lowpenetrance alleles associated with a slightly increased or decreased risk of CRC.The accumulation of low-risk variants may partly explain the familial risk of CRC,and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes.Understanding the predisposition to develop CRC will require investigators to address the following challenges:the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis;the classification of variants of unknown significance in known CRC-predisposing genes;and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers.We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of lowand moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches.Current challenges and future perspectives in the field of CRC predisposition are also discussed.展开更多
Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androg...Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.展开更多
Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation pla...Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation plays a significant role in cancer, from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis. Recent studies also suggest a role for DNA methylation in drug resistance. This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance, with a focus on breast cancer. In addition, we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance. Hormone ablation is the therapy of choice for hormone-sensitive breast tumors, yet as many as 40% of patients inevitably relapse, and these hormone refractory tumors often have a poor prognosis. Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment. Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells. Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood, and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts. Going forward, DNA methylome profiling will become increasingly central to epigenetic research, heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.展开更多
Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resul...Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer, This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.展开更多
Objective: Long non-coding RNAs(lnc RNAs) are involved in numerous biological processes in lung cancer cells. In our previous studies, we identified a lnc RNA, ENST00000439577, which is highly expressed in lung carcin...Objective: Long non-coding RNAs(lnc RNAs) are involved in numerous biological processes in lung cancer cells. In our previous studies, we identified a lnc RNA, ENST00000439577, which is highly expressed in lung carcinomas, and termed it lung cancer progression-associated transcript 1(LCPAT1). To characterize the role of LCPAT1 in lung cancer, we conducted the current study.Methods: Expression of LCPAT1 and autophagy-associated markers in tumor tissues and lung cancer cell lines was determined by real-time quantitative polymerase chain reaction(q PCR). Hematoxylin and eosin(HE) staining, q PCR, Western blot, and immunohistochemistry were performed to evaluate xenografted tumor tissues. Autophagy induced by rapamycin was detected by Western blot and immunofluorescence in lung cancer cell lines.Results: Expression of LCPAT1 and microtubule-associated protein 1 light chain 3 beta(LC3B) was positively correlated in lung cancer. Knockdown of LCPAT1 inhibited tumor growth and suppressed cell autophagy in vivo. Moreover, LCPAT1 knockdown in lung cancer cell lines resulted in decreased autophagy-associated gene expression and alleviated the cell autophagy induced by rapamycin.Conclusions: We speculate that LCPAT1 plays a crucial role in regulating autophagy in lung cancer.展开更多
Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxi...Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available drug therapy according the genetic profile. Several mechanisms have been suggested to contribute to chemo-therapeutic drug resistance: amplification or overexpression of membrane transporters, changes in cellular proteins involved in detoxification or in DNA repair, apoptosis and activation of oncogenes or tumor suppressor genes. Colorectal cancer (CRC) is regarded as intrinsically resistant to chemotherapy. Several molecular markers predictive of CRC therapy have been included during the last decade but their results in different studies complicate their application in practical clinical. The simultaneous testing of multiple markers predictive of response could help to identify more accurately the true role of these polymorphisms in CRC therapy. This review analyzes the role of genetic variants in genes involved in the action mechanisms of the drugs used at present in colorectal cancer.展开更多
Weight gain occurs in the majority of women following breast cancer treatment. An overview of studies describing weight gain amongst women treated with early to modern chemotherapy regimens is included. Populations at...Weight gain occurs in the majority of women following breast cancer treatment. An overview of studies describing weight gain amongst women treated with early to modern chemotherapy regimens is included. Populations at higher risk include women who are younger, closer to ideal body weight and who have been treated with chemotherapy. Weight gain ranges between 1 to 5 kg, and may be associated with change in body composition with gain in fat mass and loss in lean body mass. Women are unlikely to return to pre-diagnosis weight. Possible mechanisms including inactivity and metabolic changes are explored. Potential interventions are reviewed including exercise, dietary changes andpharmacologic agents. Although breast cancer prognosis does not appear to be significantly impacted, weight gain has negative consequences on quality of life and overall health. Future studies should explore change in body composition, metabolism and insulin resistance. Avoiding weight gain in breast cancer survivors following initial diagnosis and treatment should be encouraged.展开更多
AIM： To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer （GEC） in a real-world treat- ment setting. METHODS： Patients with claims between 2004...AIM： To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer （GEC） in a real-world treat- ment setting. METHODS： Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan databases. Capecitabine regimens were compared with 5-fluorouracU （5-FU） and other chemotherapy regimens, and were stratified by treatment setting. RESULTS： We identified 1013 patients with GEC： approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treat- ment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% （95% CI： 26%-81%） lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU.CONCLUSION： Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC.展开更多
Recent years have witnessed enormous progress in our understanding of the genetic predisposition to colorectal cancer (CRC). Estimates suggest that all or most genetic susceptibility mechanisms proposed so far, rangin...Recent years have witnessed enormous progress in our understanding of the genetic predisposition to colorectal cancer (CRC). Estimates suggest that all or most genetic susceptibility mechanisms proposed so far, ranging from high-penetrance genes to low-risk alleles, account for about 60% of the population-attributable fraction of CRC predisposition. In this context, there is increasing interest in the gene encoding the transforming growth factor β receptor 1 (TGFBR1 ); first when over a decade ago a common polymorphism in exon 1 (rs11466445, TGFBR1 *6A/9A) was suggested to be a risk allele for CRC, then when linkage studies identified the chromosomal region where the gene is located as susceptibility locus for familial CRC, and more recently when the allele-specific expression (ASE) of the gene was proposed as a risk factor for CRC. Published data on the association of TGFBR1 with CRC, regarding polymorphisms and ASE and including sporadic and familial forms of the disease, are often contradictory. This review gives a general overview of the most relevant studies in order to clarify the role of TGFBR1 in the field of CRC genetic susceptibility.展开更多
Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation.Unfortunately,once metastatic,no available therapy is curative.The vast majority will die despite a...Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation.Unfortunately,once metastatic,no available therapy is curative.The vast majority will die despite aggressive systemic combinational androgenablation therapies.Thus,there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer(mCRPC).To accomplish this goal,advantage can be taken of the unique biology of mCRPC cells.Like their normal cell of origin,mCRPCs retain expression of the prostate-specific differentiation protein,prostate-specific antigen(PSA),which they abundantly secrete into their extracellular fluid(ECF).This unique,and essentially universal,secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as“molecular grenades”covalently linked to cysteine-34 of human serum albumin(HSA)via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis(i.e.,“detonation”)releases the grenades restrictively within the ECF of mCRPC.This approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days(i.e.,pharmacokinetic effect)and increasing the tissue concentration of the maleimide coupled albumin delivery(MAD)in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites(i.e.,enhanced permeability and retention effect).This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic form.Only within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently“pull the pin”on the grenades releasing their lipophilic cellpenetrant toxins from HSA.Thus,if a sufficient level of“detonation”occurs,this will kill mCRPC cells,and sterilize the entire PSA-rich metastatic sites via a bystander effect.In this review,two examples of such MAD-PSA detonated molecular grenades are presenteddone based upon thapsigagin and the other on niclosamide.展开更多
BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with n...BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal(GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.AIM To analyze the role of helicase BRIP1(FANCJ) in GI cancers pathogenesis.METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic,cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.RESULTS Molecular lesions in BRIP1 were rare(3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations,40% were possibly pathogenic according to the Onco KB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.展开更多
Cellular senescence is a form of permanent cell cycle arrest that can be triggered by a variety of cell-intrinsic and extrinsic stimuli, including telomere shortening,DNA damage, oxidative stress, and exposure to chem...Cellular senescence is a form of permanent cell cycle arrest that can be triggered by a variety of cell-intrinsic and extrinsic stimuli, including telomere shortening,DNA damage, oxidative stress, and exposure to chemotherapeutic agents and ionizing radiation. Although the induction of apoptotic cell death is a desirable outcome in cancer therapy, mutations and/or deficiencies in the apoptotic signaling pathways have been frequently identified in many human cancer types,suggesting the importance of alternative apoptosis-independent therapeutic approaches for cancer treatment. A growing body of evidence has documented that senescence induction in tumor cells is a frequent response to many anticancer modalities including cyclin-dependent kinases 4/6 small molecule inhibitor-based targeted therapeutics and T helper-1 cytokine-mediated immunotherapy. This review discusses the recent advances and clinical relevance of therapy-induced senescence in cancer treatment.展开更多
Objective:Recent research has indicated that altered promoter methylation of oncogenes and tumor suppressor genes is an important mechanism in lung cancer development and progression.In this study,we investigated the ...Objective:Recent research has indicated that altered promoter methylation of oncogenes and tumor suppressor genes is an important mechanism in lung cancer development and progression.In this study,we investigated the association between promoter methylation of TMEM88,a possible inhibitor of the Wnt/β-Catenin signaling,and the survival of patients with nonsmall cell lung cancer(NSCLC).Methods:Twelve pairs of tumor and adjacent non-tumor samples were used for microarray analyses of DNA methylation and gene expression.For validation,more than two hundred additional samples were analyzed for methylation using bisulfite pyrosequencing and for gene expression using q RT-PCR.Then the cell function were tested by wound healing,transwell,CCK8 and cell cycle assay.Results:Our analysis of patient specimens showed that TMEM88 methylation was higher in NSCLC tumors(82.2%±10.3,P<0.01)compared with the adjacent normal tissues(65.9%±7.2).The survival analysis revealed that patients with high TMEM88methylation had a shorter overall survival(46 months)compared with patients with low TMEM88 methylation(>56 months;P=0.021).In addition,we found that demethylation treatment could inhibit tumor cell proliferation,migration,and invasion,which was supportive of an association between methylation and survival.Conclusions:Based on these consistent observations,we concluded that TMEM88 may play an important role in NSCLC progression and that promoter methylation of TMEM88 may serve as a biomarker for NSCLC prognosis and treatment.展开更多
AIM: To investigate whether microvessel density (MVD) is related with prognosis in gastric cancer patients, and the expression of cyclooxygenase-2 (COX-2) and vessel endothelial growth factor (VEGF) so as to determine...AIM: To investigate whether microvessel density (MVD) is related with prognosis in gastric cancer patients, and the expression of cyclooxygenase-2 (COX-2) and vessel endothelial growth factor (VEGF) so as to determine the possible role of COX-2 and VEGF in gastric cancer angiogenesis.METHODS: Forty-seven formalin-fixed paraffin-embedded tissue samples of gastric cancer were evaluated for COX-2, VEGF by immunohitochemical staining. To assess tumor angiogenesis, MVD was determined by immunohitochemical staining of endothelial protein factor Ⅷ-related antigen. The relationship among COX-2 and VEGF expression, MVD, and clinicopathologic parameters was analyzed. RESULTS: Among the 67 samples, high MVD was significantly associated with lymph node metastasis and poor survival. Multivariate survival analysis showed that MVD value and lymph node metastasis were independent prognostic factors. The expression rate of COX-2 and VEGF was significantly higher than that of the adjacent tissues. COX-2 and VEGF expression in gastric cancer was significantly correlated with tumor differentiation and depth of invasion, but not with survival. The mean MVD value of COX-2 or VEGF positive tumors was higher than that of COX-2 or VEGF negative tumors. A significant correlation was found between the expressions of COX-2and VEGF. CONCLUSION: MVD may be one of the important prognostic factors for gastric cancer patients. COX-2 and VEGF may play an important role in tumor progression by stimulating angiogenesis. VEGF might play a main role in the COX-2 angiogenic pathway. The inhibition of angiogenesis or COX-2, VEGF activity may have an important therapeutic benefit in the control of gastric cancer.展开更多
Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of acti...Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of actively moving away from the primary tumor in the first step of metastasis. Tumor budding has been observed in a variety of carcinomas and is best studied in colorectal cancers where it portends poor prognosis. More recently, tumor budding was found to be of prognostic significance in other cancers including breast cancer. Tumor budding in breast cancer is associated with other adverse pathologic factors, such as larger tumor size and lymphovascular invasion, but may have additional independent prognostic value. In the future, standardization of the quantification criteria for tumor budding may further aid in its adoption as a prognostic marker.展开更多
Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which acc...Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.展开更多
AIM： To investigate the association between individual or combined use of non-steroidal anti-inflammatory drugs （NSAIDs） or statins and colorectal cancer risk.METHODS： In a population-based case-control study in w...AIM： To investigate the association between individual or combined use of non-steroidal anti-inflammatory drugs （NSAIDs） or statins and colorectal cancer risk.METHODS： In a population-based case-control study in women, we examined the association between NSAIDs and statin use and the risk of colorectal cancers. We further investigated whether the use of statins modifies the protective effect of NSAIDs. Female cases （n = 669）of colorectal cancer aged 50-74 years were identified from a storewide registry in Wisconsin during 1999-2001. Community control women （n = 1375） were randomly selected from lists of licensed drivers and Medicare beneficiaries. Medication use and risk factor information were gathered during a structured telephone interview. A multivariable logistic regression model was used to calculate odds ratio （OR） and 95% confidence interval （CI）.RESULTS： Overall, NSAIDs users had a 30% reduction in risk of colorectal cancer （95% CI： 0.56-0.88）. Statin use was not associated with colorectal cancer risk （OR = 1.17, 95% CI： 0.74-1.85）, regardless of structural type （lipophilic or hydrophilic）, duration of use, or recency. There was no evidence of an interaction between NSAIDs and statins and colorectal cancer risk （P-interaction = 0.28）.CONCLUSION： Although our results confirm the inverse association between NSAIDs use and colorectal cancer risk, they do not support a risk reduction in statin users, or an interaction effect of combined NSAIDs and statin use.展开更多
There is now strong evidence that the paternal contribution to offspring phenotype at fertilisation is more than just DNA. However, the identity and mechanisms of this nongenetic inheritance are poorly understood. One...There is now strong evidence that the paternal contribution to offspring phenotype at fertilisation is more than just DNA. However, the identity and mechanisms of this nongenetic inheritance are poorly understood. One of the more important questions in this research area is： do changes in sperm DNA methylation have phenotypic consequences for offspring？ We have previously reported that offspring of obese male rats have altered glucose metabolism compared with controls and that this effect was inherited through nongenetic means. Here, we describe investigations into sperm DNA methylation in a new cohort using the same protocol. Male rats on a high-fat diet were 30% heavier than control-fed males at the time of mating （16-19 weeks old, n = 14/14）. A small （0.25%） increase in total 5-methyl-2＇-deoxycytidine was detected in obese rat spermatozoa by liquid chromatography tandem mass spectrometry. Examination of the repetitive fraction of the genome with methyI-CpG binding domain protein-enriched genome sequencing （MBD-Seq） and pyrosequencing revealed that retrotransposon DNA methylation states in spermatozoa were not affected by obesity, but methylation at satellite repeats throughout the genome was increased. However, examination of muscle, liver, and spermatozoa from male 27-week-old offspring from obese and control fathers （both groups from n = 8 fathers） revealed that normal DNA methylation levels were restored during offspring development. Furthermore, no changes were found in three genomic imprints in obese rat spermatozoa. Our findings have implications for transgenerational epigenetic reprogramming. They suggest that postfertilization mechanisms exist for normalising some environmentally-induced DNA methylation changes in sperm cells.展开更多
Through advances in technology,the genetic basis of cancer has been investigated at the genomic level,and many fundamental questions have begun to be addressed.Among several key unresolved questions in cancer biology,...Through advances in technology,the genetic basis of cancer has been investigated at the genomic level,and many fundamental questions have begun to be addressed.Among several key unresolved questions in cancer biology,the molecular basis for the link between nuclear deformation and malignancy has not been determined.Another hallmark of human cancer is aneuploidy;however,the causes and consequences of aneuploidy are unanswered and are hotly contested topics.We found that nuclear lamina proteins lamin A/C are absent in a significant fraction(38%) of human breast cancer tissues.Even in lamin A/C-positive breast cancer,lamin A/C expression is heterogeneous or aberrant(such as non-nuclear distribution) in the population of tumor cells,as determined by immunohistology and immunofluorescence microscopy.In most breast cancer cell lines,a significant fraction of the lamin A/C-negative population was observed.To determine the consequences of the loss of lamin A/C,we suppressed their expression by shRNA in noncancerous primary breast epithelial cells.Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation,resembling that of cancer cells,as observed by immunofluorescence microscopy.The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization.We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.展开更多
文摘Glyceraldehyde-3-phosphate dehydrogenase （GAPDH）, initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and pnsttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 （HIF-1）, p53, nitric oxide （NO）, and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications （PTMs） occurring in GAPDH in cancer cells result in new activities unrelated to the original glycnlytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described.
基金The Spanish Ministry of the Economy(State Secretariat for Research,Development and Innovation),grant SAF2012-38885Ramon y Cajal contract+1 种基金L’Oreal-UNESCO"For Women in Science"and the Scientific Foundation Asociacion Espanola Contra el Cancer
文摘The development of colorectal cancer(CRC)can be influenced by genetic factors in both familial cases and sporadic cases.Familial CRC has been associated with genetic changes in high-,moderate-and low-penetrance susceptibility genes.However,despite the availability of current gene-identification techniques,the genetic causes of a considerable proportion of hereditary cases remain unknown.Genome-wide association studies of CRC have identified a number of common lowpenetrance alleles associated with a slightly increased or decreased risk of CRC.The accumulation of low-risk variants may partly explain the familial risk of CRC,and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes.Understanding the predisposition to develop CRC will require investigators to address the following challenges:the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis;the classification of variants of unknown significance in known CRC-predisposing genes;and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers.We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of lowand moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches.Current challenges and future perspectives in the field of CRC predisposition are also discussed.
文摘Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.
基金supported in part by National Institutes of Health grants U01ES015986, U54 CA113001 and R01CA069065This TL1 award was funded by Award Number KL2 RR025754 from the National Center for Research Resources
文摘Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation plays a significant role in cancer, from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis. Recent studies also suggest a role for DNA methylation in drug resistance. This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance, with a focus on breast cancer. In addition, we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance. Hormone ablation is the therapy of choice for hormone-sensitive breast tumors, yet as many as 40% of patients inevitably relapse, and these hormone refractory tumors often have a poor prognosis. Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment. Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells. Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood, and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts. Going forward, DNA methylome profiling will become increasingly central to epigenetic research, heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.
文摘Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer, This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.
基金funded by the National Natural Science Foundation of China (Grant No. 81401046 and No.21777099)Shanghai Jiao Tong University Interdisciplinary Research Key Grant (Grant No. YG2015ZD01)Shanghai Jiao Tong University "New Young Teachers Startup Plan"
文摘Objective: Long non-coding RNAs(lnc RNAs) are involved in numerous biological processes in lung cancer cells. In our previous studies, we identified a lnc RNA, ENST00000439577, which is highly expressed in lung carcinomas, and termed it lung cancer progression-associated transcript 1(LCPAT1). To characterize the role of LCPAT1 in lung cancer, we conducted the current study.Methods: Expression of LCPAT1 and autophagy-associated markers in tumor tissues and lung cancer cell lines was determined by real-time quantitative polymerase chain reaction(q PCR). Hematoxylin and eosin(HE) staining, q PCR, Western blot, and immunohistochemistry were performed to evaluate xenografted tumor tissues. Autophagy induced by rapamycin was detected by Western blot and immunofluorescence in lung cancer cell lines.Results: Expression of LCPAT1 and microtubule-associated protein 1 light chain 3 beta(LC3B) was positively correlated in lung cancer. Knockdown of LCPAT1 inhibited tumor growth and suppressed cell autophagy in vivo. Moreover, LCPAT1 knockdown in lung cancer cell lines resulted in decreased autophagy-associated gene expression and alleviated the cell autophagy induced by rapamycin.Conclusions: We speculate that LCPAT1 plays a crucial role in regulating autophagy in lung cancer.
文摘Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available drug therapy according the genetic profile. Several mechanisms have been suggested to contribute to chemo-therapeutic drug resistance: amplification or overexpression of membrane transporters, changes in cellular proteins involved in detoxification or in DNA repair, apoptosis and activation of oncogenes or tumor suppressor genes. Colorectal cancer (CRC) is regarded as intrinsically resistant to chemotherapy. Several molecular markers predictive of CRC therapy have been included during the last decade but their results in different studies complicate their application in practical clinical. The simultaneous testing of multiple markers predictive of response could help to identify more accurately the true role of these polymorphisms in CRC therapy. This review analyzes the role of genetic variants in genes involved in the action mechanisms of the drugs used at present in colorectal cancer.
文摘Weight gain occurs in the majority of women following breast cancer treatment. An overview of studies describing weight gain amongst women treated with early to modern chemotherapy regimens is included. Populations at higher risk include women who are younger, closer to ideal body weight and who have been treated with chemotherapy. Weight gain ranges between 1 to 5 kg, and may be associated with change in body composition with gain in fat mass and loss in lean body mass. Women are unlikely to return to pre-diagnosis weight. Possible mechanisms including inactivity and metabolic changes are explored. Potential interventions are reviewed including exercise, dietary changes andpharmacologic agents. Although breast cancer prognosis does not appear to be significantly impacted, weight gain has negative consequences on quality of life and overall health. Future studies should explore change in body composition, metabolism and insulin resistance. Avoiding weight gain in breast cancer survivors following initial diagnosis and treatment should be encouraged.
文摘AIM： To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer （GEC） in a real-world treat- ment setting. METHODS： Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan databases. Capecitabine regimens were compared with 5-fluorouracU （5-FU） and other chemotherapy regimens, and were stratified by treatment setting. RESULTS： We identified 1013 patients with GEC： approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treat- ment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% （95% CI： 26%-81%） lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU.CONCLUSION： Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC.
基金Supported by The Spanish Ministry of Science and Innovation(Grant BFU2009-10281 and Ramón y Cajal contract)the Scientific Foundation of Asociación Espa ola Contra el Cáncer
文摘Recent years have witnessed enormous progress in our understanding of the genetic predisposition to colorectal cancer (CRC). Estimates suggest that all or most genetic susceptibility mechanisms proposed so far, ranging from high-penetrance genes to low-risk alleles, account for about 60% of the population-attributable fraction of CRC predisposition. In this context, there is increasing interest in the gene encoding the transforming growth factor β receptor 1 (TGFBR1 ); first when over a decade ago a common polymorphism in exon 1 (rs11466445, TGFBR1 *6A/9A) was suggested to be a risk allele for CRC, then when linkage studies identified the chromosomal region where the gene is located as susceptibility locus for familial CRC, and more recently when the allele-specific expression (ASE) of the gene was proposed as a risk factor for CRC. Published data on the association of TGFBR1 with CRC, regarding polymorphisms and ASE and including sporadic and familial forms of the disease, are often contradictory. This review gives a general overview of the most relevant studies in order to clarify the role of TGFBR1 in the field of CRC genetic susceptibility.
基金We would like to acknowledge the Prostate Cancer Foundation,Department of Defense Prostate Cancer Research Program(W81XWH-16-1-0410)NIH Prostate SPORE(P50 CA058236)Patrick C.Walsh Prostate Cancer Research Fund,and the Hopkins-Allegheny Health Network Cancer Research Fund。
文摘Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation.Unfortunately,once metastatic,no available therapy is curative.The vast majority will die despite aggressive systemic combinational androgenablation therapies.Thus,there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer(mCRPC).To accomplish this goal,advantage can be taken of the unique biology of mCRPC cells.Like their normal cell of origin,mCRPCs retain expression of the prostate-specific differentiation protein,prostate-specific antigen(PSA),which they abundantly secrete into their extracellular fluid(ECF).This unique,and essentially universal,secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as“molecular grenades”covalently linked to cysteine-34 of human serum albumin(HSA)via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis(i.e.,“detonation”)releases the grenades restrictively within the ECF of mCRPC.This approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days(i.e.,pharmacokinetic effect)and increasing the tissue concentration of the maleimide coupled albumin delivery(MAD)in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites(i.e.,enhanced permeability and retention effect).This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic form.Only within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently“pull the pin”on the grenades releasing their lipophilic cellpenetrant toxins from HSA.Thus,if a sufficient level of“detonation”occurs,this will kill mCRPC cells,and sterilize the entire PSA-rich metastatic sites via a bystander effect.In this review,two examples of such MAD-PSA detonated molecular grenades are presenteddone based upon thapsigagin and the other on niclosamide.
文摘BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal(GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.AIM To analyze the role of helicase BRIP1(FANCJ) in GI cancers pathogenesis.METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic,cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.RESULTS Molecular lesions in BRIP1 were rare(3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations,40% were possibly pathogenic according to the Onco KB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.
文摘Cellular senescence is a form of permanent cell cycle arrest that can be triggered by a variety of cell-intrinsic and extrinsic stimuli, including telomere shortening,DNA damage, oxidative stress, and exposure to chemotherapeutic agents and ionizing radiation. Although the induction of apoptotic cell death is a desirable outcome in cancer therapy, mutations and/or deficiencies in the apoptotic signaling pathways have been frequently identified in many human cancer types,suggesting the importance of alternative apoptosis-independent therapeutic approaches for cancer treatment. A growing body of evidence has documented that senescence induction in tumor cells is a frequent response to many anticancer modalities including cyclin-dependent kinases 4/6 small molecule inhibitor-based targeted therapeutics and T helper-1 cytokine-mediated immunotherapy. This review discusses the recent advances and clinical relevance of therapy-induced senescence in cancer treatment.
基金supported by the National Natural Science Foundation of China(Grant No.81573231)the Medical Professionals Crossing Project of Shanghai Jiao Tong University(Grant No.YG2015ZD01)
文摘Objective:Recent research has indicated that altered promoter methylation of oncogenes and tumor suppressor genes is an important mechanism in lung cancer development and progression.In this study,we investigated the association between promoter methylation of TMEM88,a possible inhibitor of the Wnt/β-Catenin signaling,and the survival of patients with nonsmall cell lung cancer(NSCLC).Methods:Twelve pairs of tumor and adjacent non-tumor samples were used for microarray analyses of DNA methylation and gene expression.For validation,more than two hundred additional samples were analyzed for methylation using bisulfite pyrosequencing and for gene expression using q RT-PCR.Then the cell function were tested by wound healing,transwell,CCK8 and cell cycle assay.Results:Our analysis of patient specimens showed that TMEM88 methylation was higher in NSCLC tumors(82.2%±10.3,P<0.01)compared with the adjacent normal tissues(65.9%±7.2).The survival analysis revealed that patients with high TMEM88methylation had a shorter overall survival(46 months)compared with patients with low TMEM88 methylation(>56 months;P=0.021).In addition,we found that demethylation treatment could inhibit tumor cell proliferation,migration,and invasion,which was supportive of an association between methylation and survival.Conclusions:Based on these consistent observations,we concluded that TMEM88 may play an important role in NSCLC progression and that promoter methylation of TMEM88 may serve as a biomarker for NSCLC prognosis and treatment.
基金Supported by the Major State Basic Research Development Program (973 Program) of China (No. 2003CB515507) and Science and Technology Fund by Department of Education of Anhui Province
文摘AIM: To investigate whether microvessel density (MVD) is related with prognosis in gastric cancer patients, and the expression of cyclooxygenase-2 (COX-2) and vessel endothelial growth factor (VEGF) so as to determine the possible role of COX-2 and VEGF in gastric cancer angiogenesis.METHODS: Forty-seven formalin-fixed paraffin-embedded tissue samples of gastric cancer were evaluated for COX-2, VEGF by immunohitochemical staining. To assess tumor angiogenesis, MVD was determined by immunohitochemical staining of endothelial protein factor Ⅷ-related antigen. The relationship among COX-2 and VEGF expression, MVD, and clinicopathologic parameters was analyzed. RESULTS: Among the 67 samples, high MVD was significantly associated with lymph node metastasis and poor survival. Multivariate survival analysis showed that MVD value and lymph node metastasis were independent prognostic factors. The expression rate of COX-2 and VEGF was significantly higher than that of the adjacent tissues. COX-2 and VEGF expression in gastric cancer was significantly correlated with tumor differentiation and depth of invasion, but not with survival. The mean MVD value of COX-2 or VEGF positive tumors was higher than that of COX-2 or VEGF negative tumors. A significant correlation was found between the expressions of COX-2and VEGF. CONCLUSION: MVD may be one of the important prognostic factors for gastric cancer patients. COX-2 and VEGF may play an important role in tumor progression by stimulating angiogenesis. VEGF might play a main role in the COX-2 angiogenic pathway. The inhibition of angiogenesis or COX-2, VEGF activity may have an important therapeutic benefit in the control of gastric cancer.
文摘Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of actively moving away from the primary tumor in the first step of metastasis. Tumor budding has been observed in a variety of carcinomas and is best studied in colorectal cancers where it portends poor prognosis. More recently, tumor budding was found to be of prognostic significance in other cancers including breast cancer. Tumor budding in breast cancer is associated with other adverse pathologic factors, such as larger tumor size and lymphovascular invasion, but may have additional independent prognostic value. In the future, standardization of the quantification criteria for tumor budding may further aid in its adoption as a prognostic marker.
基金Supported by In part by Georgia Cancer Coalition Distinguished Cancer Scholar award,NIH-NCRR-RCMI,No.G-12-RR003034,No.U54 RR02613,and No.5P20RR11104NIHMD research endowment,No.2S21MD000101,and No.U54CA118638ING foundation grant to Rao VN
文摘Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.
文摘AIM： To investigate the association between individual or combined use of non-steroidal anti-inflammatory drugs （NSAIDs） or statins and colorectal cancer risk.METHODS： In a population-based case-control study in women, we examined the association between NSAIDs and statin use and the risk of colorectal cancers. We further investigated whether the use of statins modifies the protective effect of NSAIDs. Female cases （n = 669）of colorectal cancer aged 50-74 years were identified from a storewide registry in Wisconsin during 1999-2001. Community control women （n = 1375） were randomly selected from lists of licensed drivers and Medicare beneficiaries. Medication use and risk factor information were gathered during a structured telephone interview. A multivariable logistic regression model was used to calculate odds ratio （OR） and 95% confidence interval （CI）.RESULTS： Overall, NSAIDs users had a 30% reduction in risk of colorectal cancer （95% CI： 0.56-0.88）. Statin use was not associated with colorectal cancer risk （OR = 1.17, 95% CI： 0.74-1.85）, regardless of structural type （lipophilic or hydrophilic）, duration of use, or recency. There was no evidence of an interaction between NSAIDs and statins and colorectal cancer risk （P-interaction = 0.28）.CONCLUSION： Although our results confirm the inverse association between NSAIDs use and colorectal cancer risk, they do not support a risk reduction in statin users, or an interaction effect of combined NSAIDs and statin use.
文摘There is now strong evidence that the paternal contribution to offspring phenotype at fertilisation is more than just DNA. However, the identity and mechanisms of this nongenetic inheritance are poorly understood. One of the more important questions in this research area is： do changes in sperm DNA methylation have phenotypic consequences for offspring？ We have previously reported that offspring of obese male rats have altered glucose metabolism compared with controls and that this effect was inherited through nongenetic means. Here, we describe investigations into sperm DNA methylation in a new cohort using the same protocol. Male rats on a high-fat diet were 30% heavier than control-fed males at the time of mating （16-19 weeks old, n = 14/14）. A small （0.25%） increase in total 5-methyl-2＇-deoxycytidine was detected in obese rat spermatozoa by liquid chromatography tandem mass spectrometry. Examination of the repetitive fraction of the genome with methyI-CpG binding domain protein-enriched genome sequencing （MBD-Seq） and pyrosequencing revealed that retrotransposon DNA methylation states in spermatozoa were not affected by obesity, but methylation at satellite repeats throughout the genome was increased. However, examination of muscle, liver, and spermatozoa from male 27-week-old offspring from obese and control fathers （both groups from n = 8 fathers） revealed that normal DNA methylation levels were restored during offspring development. Furthermore, no changes were found in three genomic imprints in obese rat spermatozoa. Our findings have implications for transgenerational epigenetic reprogramming. They suggest that postfertilization mechanisms exist for normalising some environmentally-induced DNA methylation changes in sperm cells.
基金supported by funds from concept awards BC097189 and BC076832 from Department of Defense(USA)Grants R01CA095071,R01CA099471,and CA79716to Xiang-Xi Xu from NCI
文摘Through advances in technology,the genetic basis of cancer has been investigated at the genomic level,and many fundamental questions have begun to be addressed.Among several key unresolved questions in cancer biology,the molecular basis for the link between nuclear deformation and malignancy has not been determined.Another hallmark of human cancer is aneuploidy;however,the causes and consequences of aneuploidy are unanswered and are hotly contested topics.We found that nuclear lamina proteins lamin A/C are absent in a significant fraction(38%) of human breast cancer tissues.Even in lamin A/C-positive breast cancer,lamin A/C expression is heterogeneous or aberrant(such as non-nuclear distribution) in the population of tumor cells,as determined by immunohistology and immunofluorescence microscopy.In most breast cancer cell lines,a significant fraction of the lamin A/C-negative population was observed.To determine the consequences of the loss of lamin A/C,we suppressed their expression by shRNA in noncancerous primary breast epithelial cells.Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation,resembling that of cancer cells,as observed by immunofluorescence microscopy.The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization.We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.
