Angiogenesis Related Micrornas In Hepatocellular Carcinoma (hcc) The Role And Mechanism Of Invasion And Metastasis

Hepatocellular carcinoma (HCC) is the most common liver malignancy and a major health problem globally. Current standard practices for treatment of HCC, surgical resection and liver transplantation, are less than satisfactory due to high recurrence rates. Recently, several proteins and signaling pathways have been found to correlate with the prognosis of HCC patients. Because the mechanism underlying metastasis and recurrence is not thoroughly understood, the continued search for molecular markers which predict recurrence is essential.Angiogenesis, a fundamental hallmark of cancer, can be enhanced by tumor cells and is critical to the multistep progression of cancer. Endothelial cells (ECs) play a critical role in this process as they proliferate, migrate, and line the internal surfaces of the blood vessels. An understanding of the mechanisms underlying the angiogenic activities of ECs may help us develop new strategies for targeting tumor vessels.Accumulating evidence has indicated that microRNAs play important roles in multiple physiological and pathological processes, including carcinogenesis and metastasis of cancer cells. MicroRNAs are small non-coding RNAs of20-22nucleotides that can inhibit protein expression by binding to the3’UTR of target mRNA resulting in transcriptional repression or degradation of target mRNA.This study used a microRNA array to examine the microRNA expression profile of human umbilical vein endothelial cells (HUVECs) exposed to human HCC cells comparing to HUVECs cultured alone, and identified a group of dysregulated microRNAs. We next chose the most up-regulated (miR-146a) and down-regulated (miR-302c) microRNAs for further investigation.Down-regulation of miR-146a in HUVECs impaired their angiogenic activities, reduced tumor size and angiogenesis in implanted tumors, while the up-regulation of miR-146a had the opposite effects. MicroRNA target reporter assay showed that miR-146a inhibits BRCA1by directly binding to the3’UTR of its mRNA. Futher studies revealed that Inhibition of BRCA1enhances the angiogenic activities of HUVECs.When HUVECs expressed high level of miR-302c, the expression of endothelial-mesenchymal transition (EndMT) markers were also changed: VE-Cadherin were up-regulated,β-catenin, FSP-1, and a-SMA were down-regulated. The migratory capacity of the HUVECs was weakened as well. These results indicated that miR-302c can inhibit EndMT of endothelial cells. In vivo and in vitro experiments showed that HUVECs overexpressing miR-302c can inhibit the growth of HCC cells. MicroRNA target reporter assay showed that miR-302c inhibits EndMT of endothelial cells through suppressing MTDH.We also employed a tissue microarray containing samples from323HCC patients to examine the expression of MTDH and its correlation with other clinicopathological characteristics. The results showed that the expression of MTDH was markedly higher in HCC tumors than in normal liver tissue. HCC patients with tumor expressing higher level of MTDH may suffer from more recurrence and metastasis. MTDH can promote HCC metastasis through the induction of EMT process and may be a candidate biomarker for prognosis as well as a target for therapy.