MiRNA199a-3p suppresses tumor growth, migration, invasion and angiogenesis in hepatocellular carcinoma by targeting VEGFA, VEGFR1, VEGFR2, HGF and MMP2.
MiRNA199a-3p suppresses tumor growth, migration, invasion and angiogenesis in hepatocellular carcinoma by targeting VEGFA, VEGFR1, VEGFR2, HGF and MMP2.
复制标题
DOI：
10.1038/cddis.2017.123
复制
发表时间：
2017-03-30
影响因子：
9
通讯作者：
Banerjee S
中科院分区：
文献类型：
--
作者：
Ghosh A;Dasgupta D;Ghosh A;Roychoudhury S;Kumar D;Gorain M;Butti R;Datta S;Agarwal S;Gupta S;Krishna Dhali G;Chowdhury A;Schmittgen TD;Kundu GC;Banerjee S
肿瘤-间质相互作用在肿瘤发生、发展中的重要性日益增加，提示肿瘤微环境（TME）中的信号分子可能成为肝细胞癌（HCC）有效的治疗靶点。在此，已经通过几种体外和体内测定研究了microRNA miR-199 a-3 p在TME调节和HCC发展中的作用。miR-199 a-3 p在HCC组织中的表达显著低，并且其过表达显著抑制NOD-SCID小鼠体内肿瘤生长和肺转移。在共培养试验中，内皮细胞（EC）或癌细胞（CAC）中miR-199 a-3 p表达的体外恢复显著减少了EC的迁移。再次，miR-199 a-3 p转染的EC与CAC的条件培养基（CM）或重组VEGF一起孵育减少了EC中的管形成，并且在抗VEGF抗体处理的或miR-199 a-3 p转染的CAC的CM中生长时，其也下降。此外，生物信息学和报告基因分析显示，miR-199 a-3 p抑制了CAC的VEGF分泌以及EC上的VEGFR 1和VEGFR 2表达，从而限制了CAC和EC之间的串扰。再次，在共培养试验中，miR-199 a-3 p在肝星状细胞（HSC）中的恢复降低了CAC的迁移和侵袭，而HGF的过表达增强了这一点，表明miR-199 a-3 p可能通过抑制HGF和调节基质金属蛋白酶MMP 2来阻碍HSC-CAC的串扰，随后通过酶报告试验和明胶酶谱法发现MMP 2是miR-199 a-3 p的靶点，分别因此，这些发现共同强调了miR-199 a-3 p限制HCC中的转移、侵袭和血管生成，因此其可被认为是用于管理HCC患者的强大有效治疗剂之一。
Increasing significance of tumor–stromal interaction in development and progression of cancer implies that signaling molecules in the tumor microenvironment (TME) might be the effective therapeutic targets for hepatocellular carcinoma (HCC). Here, the role of microRNA miR-199a-3p in the regulation of TME and development of HCC has been investigated by several in vitro and in vivo assays. Expression of miR-199a-3p was observed significantly low in HCC tissues and its overexpression remarkably inhibited in vivo tumor growth and metastasis to lung in NOD-SCID mice. In vitro restoration of miR-199a-3p expression either in endothelial cells (ECs) or in cancer cells (CACs) significantly diminished migration of ECs in co-culture assay. Again incubation of miR-199a-3p transfected ECs with either conditioned media (CM) of CACs or recombinant VEGF has reduced tube formation, in ECs and it was also dropped upon growth in CM of either anti-VEGF antibody-treated or miR-199a-3p-transfected CACs. In addition, bioinformatics and luciferase-reporter assays revealed that miR-199a-3p inhibited VEGF secretion from CACs and VEGFR1 and VEGFR2 expression on ECs and thus restricted cross talk between CACs and ECs. Again, restoration of miR-199a-3p in hepatic stellate cells (HSCs) reduced migration and invasion of CACs in co-culture assay, while it was enhanced by the overexpression of HGF suggesting miR-199a-3p has hindered HSC-CACs cross talk probably by inhibiting HGF and regulating matrix metalloproteinase MMP2, which were found as targets of miR-199a-3p subsequently by luciferase-reporter assay and gelatin zymography, respectively. Thus, these findings collectively highlight that miR-199a-3p restricts metastasis, invasion and angiogenesis in HCC and hence it may be considered as one of the powerful effective therapeutics for management of HCC patients.