AIM:To explore expressions of PIK3CA in the progression of gastric cancer from primary to metastasis and its effects on activation of phosphatidylinositol 3-kinase(PI3K)/Akt pathway.METHODS:mRNA and protein levels of ...AIM:To explore expressions of PIK3CA in the progression of gastric cancer from primary to metastasis and its effects on activation of phosphatidylinositol 3-kinase(PI3K)/Akt pathway.METHODS:mRNA and protein levels of PIK3CA were assessed,respectively,by real-time quantitative polymerase chain reaction and immunohistochemistry in specimens of normal gastric mucosa,primary foci and lymph node and distant metastasis of gastric cancer.Akt and phosphorylated Akt protein were also examined by Western blotting in these tissues,in order to analyze the effect of PIK3CA expression level changes on the activation of PI3K/Akt signaling pathway.RESULTS:PIK3CA mRNA in lymph node metastasis were approximately 5 and 2 folds higher,respectively,than that in the corresponding normal gastric mucosa and primary gastric cancer tissues(P<0.05),while no statistical significance was found compared with distant metastasis.Immunohistochemically,PIK3CA protein expression was discovered in 7(35%)specimens of 20 primary foci vs 10(67%)of 15 of lymph node metastasis or 11(61%)of 18 of distant metastasis(35%vs 67%,P=0.015;35%vs 61%,P=0.044).With the increased level of PIK3CA expression,the total Akt protein expression remained almost unchanged,but p-Akt protein was upregulated markedly.CONCLUSION:Increased expression of PIK3CA is expected to be a promising indicator of metastasis in gastric cancer.Up-regulation of PIK3CA may promote the metastasis of gastric cancer through aberrant activation of PI3K/Akt signaling.展开更多
AIM: To explore the effects of siRNA silencing of PIK3CA on proliferation, migration and invasion of gastric cancer cells and to investigate the underlying mechanisms. METHODS: The mutation of PIK3CA in exons 9 and 20...AIM: To explore the effects of siRNA silencing of PIK3CA on proliferation, migration and invasion of gastric cancer cells and to investigate the underlying mechanisms. METHODS: The mutation of PIK3CA in exons 9 and 20 of gastric cancer cell lines HGC-27, SGC-7901, BGC-823, MGC-803 and MKN-45 was screened by polymerase chain reaction (PCR) followed by sequencing. BGC-823 cells harboring no mutations in either of the exons, and HGC-27 cells containing PIK3CA mutations were employed in the current study. siRNA targeting PIK3CA was chemically synthesized and was transfect- ed into these two cell lines in vitro . mRNA and protein expression of PIK3CA were detected by real-time PCR and Western blotting, respectively. We also measured phosphorylation of a serine/threonine protein kinase (Akt) using Western blotting. The proliferation, migration and invasion of these cells were examined separately by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet-razolium bromide (MTT), wound healing and Transwell chambers assay. RESULTS: The siRNA directed against PIK3CA effectively led to inhibition of both endogenous mRNA and protein expression of PIK3CA, and thus significantly down-regulated phosphorylation of Akt (P < 0.05). Furthermore, simultaneous silencing of PIK3CA resulted in an obvious reduction in tumor cell proliferation activity, migration and invasion potential (P < 0.01). Intriguing, mutant HGC-27 cells exhibited stronger invasion ability than that shown by wild-type BGC-823 cells. Knockdown of PIK3CA in mutant HGC-27 cells contributed to a reduction in cell invasion to a greater extent than in non-mutant BGC-823 cells. CONCLUSION: siRNA mediated targeting of PIK3CA may specifically knockdown the expression of PIK3CA in gastric cancer cells, providing a potential implication for therapy of gastric cancer.展开更多
Breast cancer is the most common cancer worldwide.The occurrence of breast cancer is associated with many risk factors,including genetic and hereditary predisposition.Breast cancers are highly heterogeneous.Treatment...Breast cancer is the most common cancer worldwide.The occurrence of breast cancer is associated with many risk factors,including genetic and hereditary predisposition.Breast cancers are highly heterogeneous.Treatment strategies for breast cancer vary by molecular features,including activation of human epidermal growth factor receptor 2(HER2),hormonal receptors(estrogen receptor[ER]and progesterone receptor[PR]),gene mutations(e.g.,mutations of breast cancer 1/2[BRCA1/2]and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha[PIK3CA])and markers of the immune microenvironment(e.g.,tumor-infiltrating lymphocyte[TIL]and programmed death-ligand 1[PDL1]).Early-stage breast cancer is considered curable,for which local-regional therapies(surgery and radiotherapy)are the cornerstone,with systemic therapy given before or after surgery when necessary.Preoperative or neoadjuvant therapy,including targeted drugs or immune checkpoint inhibitors,has become the standard of care for most early-stage HER2-positive and triple-negative breast cancer,followed by risk-adapted post-surgical strategies.For ER-positive early breast cancer,endocrine therapy for 5-10 years is essential.Advanced breast cancer with distant metastases is currently considered incurable.Systemic therapies in this setting include endocrine therapy with targeted agents,such as CDK4/6 inhibitors and phosphoinositide 3-kinase(PI3K)inhibitors for hormone receptor-positive disease,anti-HER2 targeted therapy for HER2-positive disease,poly(ADP-ribose)polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple-negative disease.Innovation technologies of precision medicine may guide individualized treatment escalation or de-escalation in the future.In this review,we summarized the latest scientific information and discussed the future perspectives on breast cancer.展开更多
The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6...The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.展开更多
目的:检测PIK3CA、PIK3CB和多药耐药基因1(muhidrug resistance 1,MDR-1)、肺耐药蛋白(lung cancer resistance protein,LRP)、谷胱甘肽转移酶π(glutathione-S-transferaseπ,GST-π)、D N A拓扑异构酶Ⅱ(DNA topoisomeraseⅡ,TopoⅡ)...目的:检测PIK3CA、PIK3CB和多药耐药基因1(muhidrug resistance 1,MDR-1)、肺耐药蛋白(lung cancer resistance protein,LRP)、谷胱甘肽转移酶π(glutathione-S-transferaseπ,GST-π)、D N A拓扑异构酶Ⅱ(DNA topoisomeraseⅡ,TopoⅡ)在大肠癌中的表达,探讨PIK3CA、PIK3CB对大肠癌多药耐药性的影响.方法:应用免疫组织化学EnVision法检测316例大肠癌组织中PIK3CA、PIK3CB、MDR-1、LRP、GST-π和TopoⅡ的表达情况,并结合临床病理因素进行分析.结果:316例大肠癌中,PIK3CA、PIK3CB的表达与肿瘤的分化程度、淋巴结转移成正相关,其相关系数分别为0.136、0.168.MDR基因在大肠癌组织中的阳性率分别为:M D R-1为72.78%(230/316)、L R P为70.89%(224/316)、TOPⅡ为77.53%(245/316)及GST-π为76.58%(242/316).经Spearman相关性分析,PIK3CA、PIK3CB的表达与多药耐药蛋白MDR-1、LRP、GST-π的表达均成正相关,相关系数分别为0.288、0.128、0.1 9 7.3 1 6例大肠癌患者的中位生存期为60 mo,5年生存率为47.5%,Kaplan-Meier分析结果显示,PIK3CA与PIK3CB同时高表达、淋巴结转移、MDR-1(+)、GST-π(+)患者术后5年生存率明显降低.Cox比例风险模型显示,PIK3CA(+)PIK3CB(+)、淋巴结转移、MDR-1、GST-π是影响大肠癌患者预后的独立因素.结论:PIK3CA、PIK3CB与大肠癌的多药耐药密切相关,PIK3CA、PIK3CB、淋巴结转移、MDR-1、GST-π是影响大肠癌患者预后的独立因素,检测PIK3CA、PIK3CB为临床合理选择化疗药物、初步判断预后具有重要参考价值.展开更多
基金Supported by Medical Research Fund of Guangdong Province,No.A2007284Health Bureau Fund of Guangzhou,No.2009-YB-169
文摘AIM:To explore expressions of PIK3CA in the progression of gastric cancer from primary to metastasis and its effects on activation of phosphatidylinositol 3-kinase(PI3K)/Akt pathway.METHODS:mRNA and protein levels of PIK3CA were assessed,respectively,by real-time quantitative polymerase chain reaction and immunohistochemistry in specimens of normal gastric mucosa,primary foci and lymph node and distant metastasis of gastric cancer.Akt and phosphorylated Akt protein were also examined by Western blotting in these tissues,in order to analyze the effect of PIK3CA expression level changes on the activation of PI3K/Akt signaling pathway.RESULTS:PIK3CA mRNA in lymph node metastasis were approximately 5 and 2 folds higher,respectively,than that in the corresponding normal gastric mucosa and primary gastric cancer tissues(P<0.05),while no statistical significance was found compared with distant metastasis.Immunohistochemically,PIK3CA protein expression was discovered in 7(35%)specimens of 20 primary foci vs 10(67%)of 15 of lymph node metastasis or 11(61%)of 18 of distant metastasis(35%vs 67%,P=0.015;35%vs 61%,P=0.044).With the increased level of PIK3CA expression,the total Akt protein expression remained almost unchanged,but p-Akt protein was upregulated markedly.CONCLUSION:Increased expression of PIK3CA is expected to be a promising indicator of metastasis in gastric cancer.Up-regulation of PIK3CA may promote the metastasis of gastric cancer through aberrant activation of PI3K/Akt signaling.
基金Supported by Natural Science Foundation of Hunan Province, No.09JJ3060Health Bureau Fund of Guangzhou, No.201102A213006Education Bureau Fund of Guangzhou, No.10A186
文摘AIM: To explore the effects of siRNA silencing of PIK3CA on proliferation, migration and invasion of gastric cancer cells and to investigate the underlying mechanisms. METHODS: The mutation of PIK3CA in exons 9 and 20 of gastric cancer cell lines HGC-27, SGC-7901, BGC-823, MGC-803 and MKN-45 was screened by polymerase chain reaction (PCR) followed by sequencing. BGC-823 cells harboring no mutations in either of the exons, and HGC-27 cells containing PIK3CA mutations were employed in the current study. siRNA targeting PIK3CA was chemically synthesized and was transfect- ed into these two cell lines in vitro . mRNA and protein expression of PIK3CA were detected by real-time PCR and Western blotting, respectively. We also measured phosphorylation of a serine/threonine protein kinase (Akt) using Western blotting. The proliferation, migration and invasion of these cells were examined separately by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet-razolium bromide (MTT), wound healing and Transwell chambers assay. RESULTS: The siRNA directed against PIK3CA effectively led to inhibition of both endogenous mRNA and protein expression of PIK3CA, and thus significantly down-regulated phosphorylation of Akt (P < 0.05). Furthermore, simultaneous silencing of PIK3CA resulted in an obvious reduction in tumor cell proliferation activity, migration and invasion potential (P < 0.01). Intriguing, mutant HGC-27 cells exhibited stronger invasion ability than that shown by wild-type BGC-823 cells. Knockdown of PIK3CA in mutant HGC-27 cells contributed to a reduction in cell invasion to a greater extent than in non-mutant BGC-823 cells. CONCLUSION: siRNA mediated targeting of PIK3CA may specifically knockdown the expression of PIK3CA in gastric cancer cells, providing a potential implication for therapy of gastric cancer.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-014CAMS Initiative for Innovative Medicine,Grant/Award Number:CAMS-12M-1-010。
文摘Breast cancer is the most common cancer worldwide.The occurrence of breast cancer is associated with many risk factors,including genetic and hereditary predisposition.Breast cancers are highly heterogeneous.Treatment strategies for breast cancer vary by molecular features,including activation of human epidermal growth factor receptor 2(HER2),hormonal receptors(estrogen receptor[ER]and progesterone receptor[PR]),gene mutations(e.g.,mutations of breast cancer 1/2[BRCA1/2]and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha[PIK3CA])and markers of the immune microenvironment(e.g.,tumor-infiltrating lymphocyte[TIL]and programmed death-ligand 1[PDL1]).Early-stage breast cancer is considered curable,for which local-regional therapies(surgery and radiotherapy)are the cornerstone,with systemic therapy given before or after surgery when necessary.Preoperative or neoadjuvant therapy,including targeted drugs or immune checkpoint inhibitors,has become the standard of care for most early-stage HER2-positive and triple-negative breast cancer,followed by risk-adapted post-surgical strategies.For ER-positive early breast cancer,endocrine therapy for 5-10 years is essential.Advanced breast cancer with distant metastases is currently considered incurable.Systemic therapies in this setting include endocrine therapy with targeted agents,such as CDK4/6 inhibitors and phosphoinositide 3-kinase(PI3K)inhibitors for hormone receptor-positive disease,anti-HER2 targeted therapy for HER2-positive disease,poly(ADP-ribose)polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple-negative disease.Innovation technologies of precision medicine may guide individualized treatment escalation or de-escalation in the future.In this review,we summarized the latest scientific information and discussed the future perspectives on breast cancer.
文摘The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.
文摘目的:检测PIK3CA、PIK3CB和多药耐药基因1(muhidrug resistance 1,MDR-1)、肺耐药蛋白(lung cancer resistance protein,LRP)、谷胱甘肽转移酶π(glutathione-S-transferaseπ,GST-π)、D N A拓扑异构酶Ⅱ(DNA topoisomeraseⅡ,TopoⅡ)在大肠癌中的表达,探讨PIK3CA、PIK3CB对大肠癌多药耐药性的影响.方法:应用免疫组织化学EnVision法检测316例大肠癌组织中PIK3CA、PIK3CB、MDR-1、LRP、GST-π和TopoⅡ的表达情况,并结合临床病理因素进行分析.结果:316例大肠癌中,PIK3CA、PIK3CB的表达与肿瘤的分化程度、淋巴结转移成正相关,其相关系数分别为0.136、0.168.MDR基因在大肠癌组织中的阳性率分别为:M D R-1为72.78%(230/316)、L R P为70.89%(224/316)、TOPⅡ为77.53%(245/316)及GST-π为76.58%(242/316).经Spearman相关性分析,PIK3CA、PIK3CB的表达与多药耐药蛋白MDR-1、LRP、GST-π的表达均成正相关,相关系数分别为0.288、0.128、0.1 9 7.3 1 6例大肠癌患者的中位生存期为60 mo,5年生存率为47.5%,Kaplan-Meier分析结果显示,PIK3CA与PIK3CB同时高表达、淋巴结转移、MDR-1(+)、GST-π(+)患者术后5年生存率明显降低.Cox比例风险模型显示,PIK3CA(+)PIK3CB(+)、淋巴结转移、MDR-1、GST-π是影响大肠癌患者预后的独立因素.结论:PIK3CA、PIK3CB与大肠癌的多药耐药密切相关,PIK3CA、PIK3CB、淋巴结转移、MDR-1、GST-π是影响大肠癌患者预后的独立因素,检测PIK3CA、PIK3CB为临床合理选择化疗药物、初步判断预后具有重要参考价值.
