AIM： To evaluate the impact of the ITGA2 gene polymorphism on gastric cancer risk. METHODS： A hospital-based case-control study was conducted, including 307 gastric cancer patients and 307 age- and gender-matched co...AIM： To evaluate the impact of the ITGA2 gene polymorphism on gastric cancer risk. METHODS： A hospital-based case-control study was conducted, including 307 gastric cancer patients and 307 age- and gender-matched control subjects. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS： The frequencies of the wild and variant genotypes in cases were significantly different from those of controls （P = 0.019）. Compared with individuals with the wild genotype CC, subjects with the variant genotypes （CT ＋ IT） had a significantly higher risk of gastric cancer （adjusted odds ratio = 1.57, 95% CI = 1.13-2.17, P = 0.007）. In stratified analyses, the elevated gastric cancer risk was especially evident in older individuals aged 〉 58 years, nonsmokers and rural subjects. Further analyses revealed that the variant genotypes were associated with poor tumor differentiation and adjacent organ invasion in the sub-analysis of gastric cancer patients. CONCLUSION： The ITGA2 gene C807T polymorphism may be associated with an increased risk of gastric cancer, differentiation and invasion of gastric cancer.展开更多
Myocardial injury is a common disease in the plateau,especially in the lowlanders who have migrated to the plateau,in which the pathogenesis is not well understood.Here,we established a cohort of lowlanders comprising...Myocardial injury is a common disease in the plateau,especially in the lowlanders who have migrated to the plateau,in which the pathogenesis is not well understood.Here,we established a cohort of lowlanders comprising individuals from both low-altitude and high-altitude areas and conducted plasma proteomic profiling.Proteomic data showed that there was a significant shift in energy metabolism and inflammatory response in individuals with myocardial abnormalities at high altitude.Notably,integrin alpha-Ⅱb(ITGA2B)emerged as a potential key player in this context.Functional studies demonstrated that ITGA2B upregulated the transcription and secretion of interleukin-6(IL-6)through the integrin-linked kinase(ILK)/nuclear factor-κB(NF-κB)signaling axis under hypoxic conditions.Moreover,ITGA2B disrupted mitochondrial structure and function,increased glycolytic capacity,and aggravated energy reprogramming from oxidative phosphorylation to glycolysis.Leveraging the therapeutic potential of traditional Chinese medicine in cardiac diseases,we discovered that tanshinoneⅡA(TanⅡA)effectively alleviated the myocardial injury caused by the abnormally elevated expression of ITGA2B and hypobaric hypoxia exposure in mice,thus providing a novel candidate therapeutic strategy for the prevention and treatment of high-altitude myocardial injury.展开更多
Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional stu...Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.展开更多
基金Supported by The National Natural Science Foundation of Chi-na,No. 30873099Nanjing Medical University start-up research fund for Wang XRthe Natural Science Foundation of education Department,Jiangsu Province,No. 08KJB320004
文摘AIM： To evaluate the impact of the ITGA2 gene polymorphism on gastric cancer risk. METHODS： A hospital-based case-control study was conducted, including 307 gastric cancer patients and 307 age- and gender-matched control subjects. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS： The frequencies of the wild and variant genotypes in cases were significantly different from those of controls （P = 0.019）. Compared with individuals with the wild genotype CC, subjects with the variant genotypes （CT ＋ IT） had a significantly higher risk of gastric cancer （adjusted odds ratio = 1.57, 95% CI = 1.13-2.17, P = 0.007）. In stratified analyses, the elevated gastric cancer risk was especially evident in older individuals aged 〉 58 years, nonsmokers and rural subjects. Further analyses revealed that the variant genotypes were associated with poor tumor differentiation and adjacent organ invasion in the sub-analysis of gastric cancer patients. CONCLUSION： The ITGA2 gene C807T polymorphism may be associated with an increased risk of gastric cancer, differentiation and invasion of gastric cancer.
基金supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.ZYYCXTD-D-202207)the National Natural Science Foundation of China(Grant No.82204774).
文摘Myocardial injury is a common disease in the plateau,especially in the lowlanders who have migrated to the plateau,in which the pathogenesis is not well understood.Here,we established a cohort of lowlanders comprising individuals from both low-altitude and high-altitude areas and conducted plasma proteomic profiling.Proteomic data showed that there was a significant shift in energy metabolism and inflammatory response in individuals with myocardial abnormalities at high altitude.Notably,integrin alpha-Ⅱb(ITGA2B)emerged as a potential key player in this context.Functional studies demonstrated that ITGA2B upregulated the transcription and secretion of interleukin-6(IL-6)through the integrin-linked kinase(ILK)/nuclear factor-κB(NF-κB)signaling axis under hypoxic conditions.Moreover,ITGA2B disrupted mitochondrial structure and function,increased glycolytic capacity,and aggravated energy reprogramming from oxidative phosphorylation to glycolysis.Leveraging the therapeutic potential of traditional Chinese medicine in cardiac diseases,we discovered that tanshinoneⅡA(TanⅡA)effectively alleviated the myocardial injury caused by the abnormally elevated expression of ITGA2B and hypobaric hypoxia exposure in mice,thus providing a novel candidate therapeutic strategy for the prevention and treatment of high-altitude myocardial injury.
基金This manuscript has been partially supported by NIH/NCI grants R00CA160638 and R01CA245699(H.L.),and Supple-ment for Diversity(V.A.),T32 CA080621-15(R.T.),and R01CA213843(R.A.K),American Cancer Society grant ACS127951-RSG-15-025-01-CSM(H.L.)the Susan G.Komen Foundation CCR15332826(H.L.)and CCR18548501(X.L.)+3 种基金the Department of Defense W81XWH-16-1-0021(H.L.)the Lynn Sage Cancer Research Foundation(X.L.and H.L.)North-western University’s Endocrinology Training Grant T32DK007169-39(A.H.)and start-up funds fromCaseWestern Reserve University and at Northwestern University(H.L.).
文摘Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.
