Let-7g下调HMGA2抑制原发性肝细胞癌增殖、侵袭的作用及机制研究
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摘要
目的：原发性肝细胞癌(primary hepatocellular carcinoma, HCC),是我国最常见的恶性肿瘤之一,具有高发病率和高死亡率特点。因此,研究肝癌发生发展的分子机制,对提高肝癌治疗疗效有重要的临床指导意义。高迁移率族蛋白2(high-mobility groupA2, HMGA2)是一种非组蛋白染色体蛋白,在多种肿瘤中高表达,并与肿瘤预后密切相关,但在肝癌中的作用并不清楚。microRNA分子是一类非编码小RNA, let-7g作为microRNA分子一员,通过与靶基因3’非编码翻译区(3’UTR)结合抑制靶基因的转录或翻译,调控许多基因的表达。在肝癌中尚未见let-7g对HMGA2调控的研究。在本次研究中,我们首先检测HMGA2和let-7g在肝癌组织及肝癌细胞中的表达情况并分析两者的相关性,分析HMGA2蛋白的表达与肝癌临床病理参数及预后之间的关系；探讨转染let-7g mimics提高细胞内let-7g表达水平对HMGA2表达的影响,对肝癌细胞株HepG2生物学活性的影响,并进一步研究其下游作用机制。
方法：(1)收集新鲜肝癌组织及其配对的癌旁组织,肝癌细胞系并收集肝癌石蜡切片及其配对的癌旁组织。行实时荧光定量PCR (Real-time qPCR)检测HMGA2mRNA. let-7g在肝癌组织、肝癌细胞的表达水平,分析两者在肝癌组织中的相关性。行免疫组化检测HMGA2蛋白在肝癌中表达情况,分析]3MGA2蛋白表达与肝癌临床病理因素及肝癌预后之间的关系。(2)合成let-7g mimics并瞬时转染HepG2细胞。Real-time qPCR检测转染后细胞内let-7g表示水平,再行Real-time qPCR和western blot检测上调let-7g表达后对HMGA2表达的影响；行双荧光素酶报告基因实验检测let-7g对HMGA2的靶向调节作用。分别运用MTT法、流式细胞术和Transwell法检测表达上调后let-7g对细胞增殖、凋亡、侵袭和迁移的影响。(3) Real-time qPCR和western blot检测上调let-7g表达后细胞内p16基因表达情况。
结果：(1)HMGA2mRNA在肝癌组织的表达明显高于其癌旁组织中的表达；在肝癌细胞HepG2, HuH-7是高表达的,在肝细胞L02是低表达的；HMGA2在肝癌组织的表达与let-7g负相关。(2)HMGA2蛋白在肝癌组织阳性表达率明显高于癌旁组织；HMGA2蛋白的表达与肝癌的大小、血管及包膜侵犯正相关,与肝癌预后负相关。(3)通过转染let-7g mimics上调HepG2细胞内let-7g的表达水平,let-7g在转录和翻译水平抑制了HMGA2的表达,通过双荧光素酶报告基因实验证实HMGA2是let-7g靶基因。(4)上调细胞内let-7g表达水平可抑制细胞增殖、抑制细胞迁移和侵袭、促进细胞凋亡。(5)上调细胞内let-7g表达水平后,细胞中p16基因的表达水平是升高的,let-7g可通过抑制HMGA2表达,上调p16的表达。
结论：(1)HMGA2在肝癌组织中高表达,HMGA2蛋白的表达与肝癌的大小、血管侵犯、包膜侵犯正相关,与预后呈负相关；HMGA2可能与肝癌的发生、发展密切相关,并可作为判断肝癌预后指标之一。(2)let-7g靶向抑制]HMGA2转录和翻译,HMGA2是let-7g的靶基因之一。(3)过表达let-7g通过靶向作用于HMGA2,抑制肝癌HepG2细胞的增殖、侵袭和转移能力并促进细胞凋亡,let-7g可能在肝癌中具有抑癌作用。
(4) let-7g可通过靶向抑制HMGA2表达,上调p16表达抑制肝癌细胞增殖。
Objectives:Hepatocellular carcinoma (HCC), which with high incidence and mortality, is one of the most common malignant tumors in china. Therefore, it is important to study the development and progression mechanism of HCC for improving curative effects of patients. High-mobility group A2(HMGA2), as a small non-histone chromosomal protein, was highly expressed in many human tumors and associated with poor prognosis, but the role of HMGA2in HCC remained unclear. The microRNAs (miRNA), is a family of mature noncoding small RNA. Let-7g, as a member of miRNA family, by binding to the3'-untranslated regions (3'UTR) of the target mRNA, induces translational repression or mRNA degradation of many genes. However, there is no repots on the regulation of HMGA2by let-7g in HCC. In this study, we first investigated the expression of HMGA2and let-7g in human HCC tissues and cells, the relationship between HMGA2and let-7was also analyzed. Then, we analyzed HMGA2expression with respect to various clinicopathologic factors in HCC patients. By transfecting let-7g mimics into HepG2, we also analyzed the effects of overexpressed let-7g on the expression of HMGA2and the bioactivity of HepG2cell and explored possible downstream mechanism.
Methods:(1) Real-time qPCR assay was used to detect the expression level of HMGA2mRNA and let-7g between fresh HCC tissues and paired non-tumor tissues, HCC cell lines and hepatocytes respectively. HMGA2protein expression was assessed by immunohistochemical analysis of paraffin-embedded specimens of HCC and paired specimens of adjacent normal liver tissue. Correlations between HMGA2and clinicopathologic features and prognosis were also tested.(2) Let-7g mimics was designed and synthesized, and transfected into HepG2cells. Real-time qPCR and western blot were used to detect the effects of overexressed let-7g on HMGA2expression. Luciferase reporter assay was performed to detect whether the HMGA2was regulated by let-7g. In vitro, cell proliferation, apoptosis and migration and invasive ability were assessed by MTT assay, flow cytometry and transwell assay respectively.(3) Real-time qPCR and western blot were performed to detect p16expression after transfection of let-7g mimics into HepG2.
Results:(1) The expression of HMGA2mRNA was upregulated in HCC tissues and cell lines than in paried non-tumor tissues and hepatocytes respectively. While the expression level of let-7g was higher in non-tumor tissues than in HCC tissues. An inverse correlation was noted between HMGA2mRNA and let-7g in HCC tissues. The positive expression of HMGA2in HCC was higher than in paired specimens of adjacent normal liver tissue. Elevated HMGA2protein expression was significantly correlated with tumor size, vascular invasion and capsule invasion and poor clinical prognosis.(2) With upregulation of endogenous let-7g through transfected let-7g mimics, there was a significant downregulation of HMGA2mRNA and protein expression levels in HepG2cells. The luciferase reporter assay confirmed that HMGA2was a target of let-7g. Overexpression of let-7g inhibited the proliferation, migration, and invasion of HCC cells and increased cell apoptosis.(3) Real-time qPCR and western blot analysis showed that the mRNA and protein levels of p16were significantly increased after the upregulation of let-7g by transfecting let-7g mimics into HepG2cell.
Conclusions:(1) HMGA2was significantly upregulated in HCC. Overexpressed HMGA2was associated with tumor size, vascular invasion and capsule invasion and poor prognosis. Overexpression of HMGA2might be associated with HCC development and progress and HMGA2expression status could be served as an independent prognostic factor in HCC.(2) Overexpression of let-7g could inhibit expression of HMGA2mRNA and protein in HepG2cells and HMGA2was a target of let-7g. Overexpressed let-7g could inhibit the proliferation, migration and invasion and induce apoptosis of HepG2cells, indicating that let-7g could serve as a tumor suppressor gene in HCC.(4) let-7g could inhibit proliferation of hepatocellular carcinoma cells by downregulation of HMGA2and upregulation of p16.
方法：(1)收集新鲜肝癌组织及其配对的癌旁组织,肝癌细胞系并收集肝癌石蜡切片及其配对的癌旁组织。行实时荧光定量PCR (Real-time qPCR)检测HMGA2mRNA. let-7g在肝癌组织、肝癌细胞的表达水平,分析两者在肝癌组织中的相关性。行免疫组化检测HMGA2蛋白在肝癌中表达情况,分析]3MGA2蛋白表达与肝癌临床病理因素及肝癌预后之间的关系。(2)合成let-7g mimics并瞬时转染HepG2细胞。Real-time qPCR检测转染后细胞内let-7g表示水平,再行Real-time qPCR和western blot检测上调let-7g表达后对HMGA2表达的影响；行双荧光素酶报告基因实验检测let-7g对HMGA2的靶向调节作用。分别运用MTT法、流式细胞术和Transwell法检测表达上调后let-7g对细胞增殖、凋亡、侵袭和迁移的影响。(3) Real-time qPCR和western blot检测上调let-7g表达后细胞内p16基因表达情况。
结果：(1)HMGA2mRNA在肝癌组织的表达明显高于其癌旁组织中的表达；在肝癌细胞HepG2, HuH-7是高表达的,在肝细胞L02是低表达的；HMGA2在肝癌组织的表达与let-7g负相关。(2)HMGA2蛋白在肝癌组织阳性表达率明显高于癌旁组织；HMGA2蛋白的表达与肝癌的大小、血管及包膜侵犯正相关,与肝癌预后负相关。(3)通过转染let-7g mimics上调HepG2细胞内let-7g的表达水平,let-7g在转录和翻译水平抑制了HMGA2的表达,通过双荧光素酶报告基因实验证实HMGA2是let-7g靶基因。(4)上调细胞内let-7g表达水平可抑制细胞增殖、抑制细胞迁移和侵袭、促进细胞凋亡。(5)上调细胞内let-7g表达水平后,细胞中p16基因的表达水平是升高的,let-7g可通过抑制HMGA2表达,上调p16的表达。
结论：(1)HMGA2在肝癌组织中高表达,HMGA2蛋白的表达与肝癌的大小、血管侵犯、包膜侵犯正相关,与预后呈负相关；HMGA2可能与肝癌的发生、发展密切相关,并可作为判断肝癌预后指标之一。(2)let-7g靶向抑制]HMGA2转录和翻译,HMGA2是let-7g的靶基因之一。(3)过表达let-7g通过靶向作用于HMGA2,抑制肝癌HepG2细胞的增殖、侵袭和转移能力并促进细胞凋亡,let-7g可能在肝癌中具有抑癌作用。
(4) let-7g可通过靶向抑制HMGA2表达,上调p16表达抑制肝癌细胞增殖。
Objectives:Hepatocellular carcinoma (HCC), which with high incidence and mortality, is one of the most common malignant tumors in china. Therefore, it is important to study the development and progression mechanism of HCC for improving curative effects of patients. High-mobility group A2(HMGA2), as a small non-histone chromosomal protein, was highly expressed in many human tumors and associated with poor prognosis, but the role of HMGA2in HCC remained unclear. The microRNAs (miRNA), is a family of mature noncoding small RNA. Let-7g, as a member of miRNA family, by binding to the3'-untranslated regions (3'UTR) of the target mRNA, induces translational repression or mRNA degradation of many genes. However, there is no repots on the regulation of HMGA2by let-7g in HCC. In this study, we first investigated the expression of HMGA2and let-7g in human HCC tissues and cells, the relationship between HMGA2and let-7was also analyzed. Then, we analyzed HMGA2expression with respect to various clinicopathologic factors in HCC patients. By transfecting let-7g mimics into HepG2, we also analyzed the effects of overexpressed let-7g on the expression of HMGA2and the bioactivity of HepG2cell and explored possible downstream mechanism.
Methods:(1) Real-time qPCR assay was used to detect the expression level of HMGA2mRNA and let-7g between fresh HCC tissues and paired non-tumor tissues, HCC cell lines and hepatocytes respectively. HMGA2protein expression was assessed by immunohistochemical analysis of paraffin-embedded specimens of HCC and paired specimens of adjacent normal liver tissue. Correlations between HMGA2and clinicopathologic features and prognosis were also tested.(2) Let-7g mimics was designed and synthesized, and transfected into HepG2cells. Real-time qPCR and western blot were used to detect the effects of overexressed let-7g on HMGA2expression. Luciferase reporter assay was performed to detect whether the HMGA2was regulated by let-7g. In vitro, cell proliferation, apoptosis and migration and invasive ability were assessed by MTT assay, flow cytometry and transwell assay respectively.(3) Real-time qPCR and western blot were performed to detect p16expression after transfection of let-7g mimics into HepG2.
Results:(1) The expression of HMGA2mRNA was upregulated in HCC tissues and cell lines than in paried non-tumor tissues and hepatocytes respectively. While the expression level of let-7g was higher in non-tumor tissues than in HCC tissues. An inverse correlation was noted between HMGA2mRNA and let-7g in HCC tissues. The positive expression of HMGA2in HCC was higher than in paired specimens of adjacent normal liver tissue. Elevated HMGA2protein expression was significantly correlated with tumor size, vascular invasion and capsule invasion and poor clinical prognosis.(2) With upregulation of endogenous let-7g through transfected let-7g mimics, there was a significant downregulation of HMGA2mRNA and protein expression levels in HepG2cells. The luciferase reporter assay confirmed that HMGA2was a target of let-7g. Overexpression of let-7g inhibited the proliferation, migration, and invasion of HCC cells and increased cell apoptosis.(3) Real-time qPCR and western blot analysis showed that the mRNA and protein levels of p16were significantly increased after the upregulation of let-7g by transfecting let-7g mimics into HepG2cell.
Conclusions:(1) HMGA2was significantly upregulated in HCC. Overexpressed HMGA2was associated with tumor size, vascular invasion and capsule invasion and poor prognosis. Overexpression of HMGA2might be associated with HCC development and progress and HMGA2expression status could be served as an independent prognostic factor in HCC.(2) Overexpression of let-7g could inhibit expression of HMGA2mRNA and protein in HepG2cells and HMGA2was a target of let-7g. Overexpressed let-7g could inhibit the proliferation, migration and invasion and induce apoptosis of HepG2cells, indicating that let-7g could serve as a tumor suppressor gene in HCC.(4) let-7g could inhibit proliferation of hepatocellular carcinoma cells by downregulation of HMGA2and upregulation of p16.
引文
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