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Under-expression of LKB1 is associated with enhanced p38-MAPK signaling in human hepatocellular carcinoma.

ABSTRACT: The tumor suppressor liver kinase B1 (LKB1), a highly conserved and ubiquitously expressed protein kinase, plays a critical role in tumorigenesis. LKB1 has recently been identified in tumorigenesis of several cancers including lung cancer, breast cancer, and pancreatic cancer. However, the role of LKB1 in hepatocellular carcinoma (HCC) remains unclear. Herein, we examined the expression levels of LKB1 in HCC patients and cell lines by quantitative real-time PCR (qRT-PCR) and western blot analysis. Furthermore, LKB1 protein expression was analyzed in archived paraffin-embedded HCC tissues using immunohistochemistry (IHC), and its association with overall survival was shown in statistical analysis. In vitro assays, including RNAi studies, were performed to further explore the role of LKB1 in tumor progression in HCC cell lines. Our results revealed that the expression of LKB1 was lower in HCC tissue and cell lines than in corresponding adjacent normal tissue and normal human liver cell line (HL7702). Moreover, HCC patients with low LKB1 expression had advanced clinical stage and worse prognosis than those with higher LKB1 expression. Furthermore, siRNA-mediated knockdown of LKB1 resulted in enhanced cell proliferation, migration, and invasion of HCC cells. Additionally, the expression level of LKB1 positively correlated with E-cadherin levels, wherein siRNA-transfected cells exhibited significantly decreased levels of E-cadherin, while phosphorylated p38 and vimentin levels were enhanced. Inhibition of p38 MAPK signaling was capable of reversing E-cadherin up-regulation and vimentin down-regulation. In all, our results indicate that LKB1 acts as a tumor suppressor gene, which may inhibit EMT through the p38 MAPK signaling pathway involved in HCC progression.

SUBMITTER: Sha L

PROVIDER: S-EPMC6963048 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Under-expression of LKB1 is associated with enhanced p38-MAPK signaling in human hepatocellular carcinoma.

Sha Liang L Lian Fang F Li Kezhi K Chen Chuang C Zhao Yinnong Y He Jianbo J Huang Shan S Wu Guobin G

International journal of clinical and experimental pathology 20181101 11

The tumor suppressor liver kinase B1 (LKB1), a highly conserved and ubiquitously expressed protein kinase, plays a critical role in tumorigenesis. LKB1 has recently been identified in tumorigenesis of several cancers including lung cancer, breast cancer, and pancreatic cancer. However, the role of LKB1 in hepatocellular carcinoma (HCC) remains unclear. Herein, we examined the expression levels of LKB1 in HCC patients and cell lines by quantitative real-time PCR (qRT-PCR) and western blot analysi ...[more]

PMID: 31949640

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Project description:The CXCL12/CXCR4 axis has been posited widely to have significant roles in many primary tumors and metastases. It is known that CXCR7 can also be engaged by CXCL12, but the exact function of CXCR7 is controversial. This prompted us to investigate the expression, specific function and signal transduction of CXCR7 in hepatocellular carcinoma (HCC). In this study, CXCR7 and CXCR4 were differentially expressed in nine cell lines of HCC, and that elevated expression of both CXCR7 and CXCL4 were correlated with highly metastatic ability of HCC cells. Moreover, CXCR7 expression was significantly upregulated in metastatic HCC samples compared with the non-metastatic ones by staining of high-density tissue microarrays constructed from a cohort of 48 human HCC specimens. CXCR7 overexpression enhanced cell growth and invasiveness in vitro, and tumorigenicity and lung metastasis in vivo. By contrast, CXCR7 stable knockdown markedly reduced these malignant behaviors. In addition, it was observed that alterations in CXCR7 expression were positively correlated with the phosphorylation levels of mitogen-activated protein kinase (MAPK) pathway proteins. Targeting extracellular regulated kinase pathway by using U0126 inhibitor or using CCX771, a selective CXCR7 antagonist, drastically reduced CXCR7-mediated cell proliferation. Importantly, by using human biotin-based antibody arrays, several differentially expressed proteins were identified in CXCR7-overexpression and depletion groups. Comparative analysis indicated that upstream regulators including TP53 and IL-6 were involved in CXCR7 signal transduction. CXCR7 expression was further proved to regulate expression of vascular endothelial growth factor A and galectin-3, which may contribute to tumor angiogenesis and invasiveness. Consequently, elevated expression of CXCR7 contributes to HCC growth and invasiveness via activation of MAPK and angiogenesis signaling pathways. Targeting CXCR7 may prevent metastasis and provide a potential therapeutic strategy for HCC.

Dataset Information

Under-expression of LKB1 is associated with enhanced p38-MAPK signaling in human hepatocellular carcinoma.

Publications

Under-expression of LKB1 is associated with enhanced p38-MAPK signaling in human hepatocellular carcinoma.

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