Objective:To explore the changes in the expression of autophagy-related protein BECN1 and tumor-associated macrophage marker CD68 in colorectal cancer and investigate their association with clinicopathological feature...Objective:To explore the changes in the expression of autophagy-related protein BECN1 and tumor-associated macrophage marker CD68 in colorectal cancer and investigate their association with clinicopathological features and prognosis in colorectal cancer patients.Methods:Sixty colorectal cancer patients were selected as study subjects.Immunohistochemistry was used to detect the expression of BECN1 and CD68 in both colorectal cancer tissues and adjacent non-cancerous tissues.Based on immunohistochemistry results,patients were divided into a BECN1 high-expression group(33 cases)and low-expression group(27 cases)and a CD68 high-expression group(33 cases)and low-expression group(27 cases).Survival rates and survival times of the two groups were compared using the Kaplan-Meier survival curve and Log-Rank test.The correlation between BECN1 and CD68 expression in colorectal cancer tissues was analyzed.RT-qPCR was employed to examine changes in macrophage-associated markers after BECN1 interference.Results:Expression levels of BECN1 and CD68 in colorectal cancer tissues were significantly higher than those in adjacent tissues and were positively correlated with the TNM stage.Survival analysis showed that patients in the BECN1 and CD68 high-expression groups had shorter overall survival compared to those in the low-expression group(P<0.05).BECN1 and CD68 levels in colorectal cancer patients were positively correlated(P<0.001).BECN1 interference markedly reduced the expression of macrophage markers and decreased M2 polarization.Conclusion:Abnormal expression of BECN1 and CD68 in colorectal cancer patients is associated with TNM stage and poor prognosis,suggesting that BECN1 and CD68 can serve as important indicators for postoperative prognostic evaluation.展开更多
Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GG...Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.展开更多
基金National Natural Science Foundation of China Youth Fund Project(82203543)Shandong Provincial Natural Science Foundation Youth Fund Project(ZR2022QH267)+2 种基金Shandong Provincial Innovation Development Joint Fund Project(ZR2023LZL008)Binzhou Medical University Research Start-up Fund Project(50012304458)Shandong Province Medical and Health Science and Technology Project(202309030619)。
文摘Objective:To explore the changes in the expression of autophagy-related protein BECN1 and tumor-associated macrophage marker CD68 in colorectal cancer and investigate their association with clinicopathological features and prognosis in colorectal cancer patients.Methods:Sixty colorectal cancer patients were selected as study subjects.Immunohistochemistry was used to detect the expression of BECN1 and CD68 in both colorectal cancer tissues and adjacent non-cancerous tissues.Based on immunohistochemistry results,patients were divided into a BECN1 high-expression group(33 cases)and low-expression group(27 cases)and a CD68 high-expression group(33 cases)and low-expression group(27 cases).Survival rates and survival times of the two groups were compared using the Kaplan-Meier survival curve and Log-Rank test.The correlation between BECN1 and CD68 expression in colorectal cancer tissues was analyzed.RT-qPCR was employed to examine changes in macrophage-associated markers after BECN1 interference.Results:Expression levels of BECN1 and CD68 in colorectal cancer tissues were significantly higher than those in adjacent tissues and were positively correlated with the TNM stage.Survival analysis showed that patients in the BECN1 and CD68 high-expression groups had shorter overall survival compared to those in the low-expression group(P<0.05).BECN1 and CD68 levels in colorectal cancer patients were positively correlated(P<0.001).BECN1 interference markedly reduced the expression of macrophage markers and decreased M2 polarization.Conclusion:Abnormal expression of BECN1 and CD68 in colorectal cancer patients is associated with TNM stage and poor prognosis,suggesting that BECN1 and CD68 can serve as important indicators for postoperative prognostic evaluation.
文摘目的:检测BECN1、膜型微管相关蛋白1轻链3(LC3B)和雷帕霉素靶蛋白(m TOR)在宫颈鳞状上皮病变中的表达,并探讨其临床意义。方法:免疫组化法及荧光原位杂交技术检测宫颈鳞状上皮病变和正常宫颈组织中自噬相关基因BECN1、LC3B和m TOR的蛋白及m RNA表达情况。结果:宫颈鳞状细胞癌(SCC)组和高级别鳞状上皮内病变(HSIL)组中BECN1和LC3B的蛋白及m RNA表达均明显低于正常宫颈组,m TOR的蛋白及m RNA表达明显高于正常宫颈组,差异均有统计学意义(P<0.01)。低级别鳞状上皮内病变(LSIL)组中,BECN1及LC3B的蛋白表达明显低于正常宫颈组,LC3B m RNA表达明显低于正常宫颈组,m TOR m RNA表达高于正常宫颈组,差异均有统计学意义(P<0.01)。SCC组中,BECN1蛋白表达与临床分期及淋巴结转移有关,LC3B蛋白表达与肿瘤细胞分化程度相关,m TOR蛋白表达则与淋巴结转移相关。SCC组中,LC3B表达与BECN1呈正相关,与m TOR呈负相关。结论:自噬相关基因与宫颈鳞状上皮病变的严重程度有关,推测BECN1、LC3B和m TOR异常表达可能导致病变恶化。
基金This work was supported by the National Natural Science Foundation of China(Nos.82022022,32371018 and 82071274)a Project Funded by Jiangsu Key Laboratory of Neuropsychiatric Diseases(BM2013003,China)+4 种基金a Key Project of Natural Science Foundation of Jiangsu Provincial Higher Education Institutions(23KJA310005,China)a Project Funded by the Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University(MP13202823,China)a Project Funded by the Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and a Project Funded by the Priority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD).J.H.M.P.was supported Science Foundation Ireland(17/COEN/3474,17/JPND/3455)Q.M.is a recipient of an RCSI International StAR Ph.D.scholarship.N.L.was supported by the Postgraduate Research&Practice Innovation Program of Jiangsu Province.K.Y.T.,was supported by the financial support from the Science and Technology Development Fund,Macao SAR(File no.0062/2021/A,China)University of Macao(File no.MYRG2022-00171-FHS,China).
文摘Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.
