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Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways.

ABSTRACT: Advanced hepatocellular carcinoma (HCC) is an important cause of cancer mortality. Epithelial-mesenchymal transition (EMT) has been shown to be an important biological process in cancer progression and metastasis. We have focused on elucidating factors that induce EMT to promote carcinogenesis and subsequent metastasis in HCC using the BNL CL.2 (BNL) and BNL 1ME A. 7R.1 (1MEA) cell lines. BNL cells are normal hepatocytes whereas the 1MEA cells are HCC cells derived from chemical transformation of the BNL cells. Their morphological characteristics were examined. Expression levels of hepatocyte growth factor (HGF), markers of EMT and mediators of HGF signaling were determined and functional characteristics were compared. BNL cells were treated with HGF and effects on EMT-marker and mediators of HGF signaling were analyzed. BNL cells display characteristic epithelial morphology whereas 1MEA cells display mesenchymal characteristics. 1MEA cells express and secrete more HGF than BNL cells. There was significantly decreased expression of E-cadherin, albumin, AAT and increased expression of fibronectin, collagen-1, vimentin, snail and slug in 1MEA cells. There was also increased expression of cyclooxygenase-2 (COX-2), Akt and phosphorylated Akt (pAkt) in 1MEA cells. Moreover, 1MEA cells had increased migratory capacity inhibited by inhibition of COX-2 and Akt but not extracellular signal regulated kinase (ERK). Molecular mesenchymal characteristics of 1MEA cells were reversed by inhibition of COX-2, Akt and ERK. Treatment of BNL cells with HGF led to decreased expression of E-cadherin and increased expression of fibronectin, vimentin, snail, slug, COX-2, Akt, pAkt and increased migration, invasiveness and clonogenicity. We conclude that development of HCC is associated with upregulation of HGF which promotes EMT and carcinogenesis via upregulation of COX-2 and Akt. Consequently, HGF signaling may be targeted for therapy in advanced and metastatic HCC.

SUBMITTER: Ogunwobi OO

PROVIDER: S-EPMC3732749 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways.

Ogunwobi Olorunseun O OO Liu Chen C

Clinical & experimental metastasis 20110710 8

Advanced hepatocellular carcinoma (HCC) is an important cause of cancer mortality. Epithelial-mesenchymal transition (EMT) has been shown to be an important biological process in cancer progression and metastasis. We have focused on elucidating factors that induce EMT to promote carcinogenesis and subsequent metastasis in HCC using the BNL CL.2 (BNL) and BNL 1ME A. 7R.1 (1MEA) cell lines. BNL cells are normal hepatocytes whereas the 1MEA cells are HCC cells derived from chemical transformation o ...[more]

PMID: 21744257

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Project description:The present study aimed to investigate the mechanism by which cyclooxygenase?2 (COX?2) promotes the metastasis of MG?63 osteosarcoma cells through the PI3K/AKT/NF??B pathway. To achieve this, a recombinant lentivirus containing the COX?2 gene was constructed in order to overexpress COX?2; a recombinant lentivirus containing a control sequence was also constructed. A Transwell chamber migration assay was performed to quantify the migration of the COX?2?transduced cells, and of cells treated with a COX?2 inhibitor (NS398) or a PI3K inhibitor (LY294002). Immunofluorescence assays were performed to determine changes in E?cadherin, vimentin and NF??B expression levels. ELISAs were performed to quantify the levels of matrix metallopeptidase (MMP)?2, MMP?9 and vascular endothelial growth factor (VEGF) in the culture medium. Western blot analysis was conducted to measure the protein expression levels of MMP?2, MMP?9, PI3K, phosphorylated (p?) PI3K, AKT, p?AKT, inhibitor of NF??? kinase (IKK) and p?IKK. The results demonstrated that the migration ability of the COX?2?overexpressing MG?63 cells was significantly increased compared with the control cells. The migration ability of cells treated with NS398 or LY294002 was significantly decreased. Compared with the control cells, E?cadherin expression was significantly decreased in COX?2?overexpressing cells, while the expression levels of vimentin, MMP?2, MMP?9, VEGF, p?PI3K, p?AKT and p?IKK were significantly increased. Compared with the control cells, E?cadherin expression was significantly increased in cells treated with NS398 or LY294002, while the expression levels of vimentin, MMP?2, MMP?9, VEGF, p?PI3K, p?AKT, and p?IKK were significantly decreased. The total protein levels of PI3K, AKT and IKK were not changed among the treatment groups. In summary, COX?2 overexpression decreased the expression levels of the epithelial protein E?cadherin and increased the expression levels of the mesenchymal proteins vimentin, MMP?2 and MMP?9, as well as promoted cell migration, by activating the PI3K/AKT/NF??B signaling pathway.

Project description:BackgroundColorectal cancer (CRC) is the third most common cancer worldwide. Many recent studies have demonstrated that different long non-coding RNAs (lncRNAs) are involved in the initiation, advancement, and metastasis of many cancers including CRC. Cancer susceptibility candidate 9 (CASC9) is an lncRNA that has been reported in many cancers, but its role in CRC is poorly understood. In this study, we aimed to examine the expression of CASC9 in CRC cell lines and to determine the mechanism of action of CASC9 in CRC carcinogenesis.MethodsThe expression of CASC9 in CRC tissues was compared with normal samples from publicly available datasets in The Cancer Genome Atlas (TCGA) and The Encyclopedia of RNA Interactomes (ENCORI). CASC9 expression was further verified in four CRC cell lines (DLD1, HT-29, SW480, and HCT-116) and normal colorectal cell line (CCD-112CoN) by real-time quantitative polymerase chain reaction (RT-qPCR). After gene silencing in HCT-116 and SW480, Cell Counting Kit-8 assay, clonogenic assay, and wound healing assay were performed to evaluate cell proliferation, viability, and migration index of cells. Western blotting was used to explore the key pathways involved.ResultsCASC9 was significantly upregulated as analyzed from both public datasets TCGA and ENCORI where its overexpression was associated with poor survival of CRC patients. Similarly, CASC9 was significantly overexpressed in the CRC cell lines compared with normal cells studied. The silencing of CASC9 in HCT-116 and SW480 attenuated cell proliferation and migration significantly. Furthermore, pathways investigations showed that silencing of CASC9 significantly induced autophagy, promoted AMP-activated protein kinase (AMPK) phosphorylation, inhibited mTOR and AKT signaling pathways, and altered epithelial-mesenchymal transition (EMT) marker protein expression.ConclusionWe demonstrated that silencing of CASC9 contributes to the reduced CRC cell proliferation and migration by regulating autophagy and AKT/mTOR/EMT signaling. Therefore, CASC9 plays an important role in carcinogenesis, and its expression may act as a prognostic biomarker and a potential therapeutic target of CRC management.

Dataset Information

Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways.

Publications

Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways.

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