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| Six2 is negatively correlated with prognosis and facilitates epithelial-mesenchymal transition via TGF-β/Smad signal pathway in hepatocellular carcinoma |
| Zheng-Hua Wan a , b , c , Yun-Han Ma a , b , Tian-Yi Jiang a , b , Yun-Kai Lin a , b , Yuan-Yuan Shi a , Ye-Xiong Tan b , Li-Wei Dong a , Hong-Yang Wang a , b , d , ∗ |
a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China
b National Center for Liver Cancer, The Second Military Medical University, Shanghai 201805, China
c No.971 Hospital of Peoples’ Liberation Army Navy, Qingdao 266071, China
d State Key Laboratory of Oncogenes and related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
∗ Corresponding author at: National Center for Liver Cancer, The Second Military Medical University, Shanghai 201805, China.
E-mail address: hywangk@vip.sina.com (H.-Y. Wang). |
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Abstract Background: Increasing evidence indicates that Six2 contributes to tumorigenesis in various tumor including hepatocellular carcinoma (HCC). This study aimed to determine the role of Six2 in HCC and to elucidate the association of Six2 with clinical pathological characteristics.
Methods: The expressions of Six2 in HCC tumor, para-tumor tissue and portal vein tumor thrombus (PVTT) were detected by tissue microarray technique, immunohistochemistry, real-time RT-PCR and Western blotting. Chi-square and Kaplan-Meier analysis were used to analyze the correlation between Six2 expression and prognosis of HCC patients. Lentivirus mediated Six2 knockdown, spheroid formation assay, proliferation assay and subcutaneous tumor implantation were performed to determine the function of Six2.
Results: In 274 HCC samples, Six2 was strongly expressed. Kaplan-Meier analysis revealed that high ex- pression of Six2 was correlated with a shorter overall survival (OS) and disease-free survival (DFS). Moreover, Six2 expression was associated with sex, alpha-fetoprotein, tumor size and portal vein invasion. Six2 was highly expressed in PVTT. Six2 knockdown inhibited HCC cell lines proliferation, migration, and self-renewal in vitro and in vivo. In addition, low-expression of Six2 weakened TGF-β induced Smad4 activation and epithelial-mesenchymal transition in HCC cell lines.
Conclusions: Elevated Six2 expression in HCC tumor patients was associated with negative prognosis. Upregulated Six2 promoted tumor growth and facilitated HCC metastasis via TGF-β/Smad signal pathway.
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2019, Vol. 18 
