Ventilagolin Suppresses Migration, Invasion and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma Cells by Downregulating Pim-1

Abstract

Inhibition of tumor metastasis is a useful strategy to improve the efficacy of cancer therapy. Ventilagolin, a natural 1, 4-naphthoquinone derivative extracted from Ventilago leiocarpa Benth, has shown promising antitumor effects in previous studies. However, the effects and underlying mechanisms of Ventilagolin against migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) remain unclear. The present study has examined these effects and determined whether the protooncogene Pim-1 is involved. Methods: The effects of Ventilagolin on migration, invasion, Pim-1 and EMT-related proteins (eg, E-cadherin, N-cadherin, Vimentin) expression were assessed by scratch wound healing, Transwell, qRT-PCR and Western blot assays, respectively. Pim-1 stably overexpressed HepG2 and SMMC-7721 cells were generated to explore whether Ventilagolin inhibited migration, invasion and EMT of HCC cells via regulating Pim-1. Subcutaneous xenograft tumor model in nude mice was established. Histopathological changes of tumor tissues were examined by H&E staining and expressions of Pim-1 and EMT-related proteins were detected by immunohistochemistry. Results: Ventilagolin significantly (P < 0.01) reduced the expression of Pim-1 levels in HepG2 and SMMC-7721 cells. Compared with the control group, the migration and invasion abilities of Pim-1-overexpressing HepG2 and SMMC-7721 cells were significantly (P < 0.05, P < 0.01) enhanced, the expression of E-cadherin was decreased (P < 0.01), and the levels of N-cadherin and Vimentin were upregulated (P < 0.05, P < 0.01). Ventilagolin treatment effectively reversed these effects of Pim-1 overexpression. In vivo experiments showed that Ventilagolin could effectively suppress HCC tumor growth, downregulate Pim-1, N-cadherin and Vimentin expression, and upregulate E-cadherin expression. Conclusion: Ventilagolin suppresses HCC cell proliferation, migration and invasion and reverses EMT process by downregulating Pim-1, suggesting Ventilagolin is a potential therapeutic agent for treatment of HCC.

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

“…In different hematological malignancies such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, and leukemia, as well as solid tumors including prostate, colon, pancreatic, hepatocellular, and breast tumors, both PIM-1 and PIM-2 kinases are often overexpressed. It was also recently reported that PIM-1 may function as an oncogene in cervical cancer by activating EGFR signaling. − In addition, PIM-1 kinase has also been associated with various functional aspects such as immunotherapy, aging, and epigenetics . On the other hand, PIM-3 kinase is predominantly overexpressed in solid tumors derived from the prostate, pancreas, and colon.…”

Therapeutic Effects of Natural Products on Liver Cancer and Their Potential Mechanisms

“…The alkaloid CVB-D suppresses proliferation, migration, invasion, and EMT of HCC cell lines by inhibiting the EGFR-FAK-AKT/ERK1/2-Slug signaling pathway in human HCC [ 99 ]. Both in vivo and in vitro studies demonstrate that the alkaloid ventilagolin downregulates the expression of Pim-1, N -cadherin, and vimentin, upregulates the expression of E-cadherin, and inhibits the migration, invasion, and EMT of HCC cells [ 103 ]. These studies collectively confirm that NPs can exert anti-tumor effects by inhibiting migration and invasion.…”