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The semaphorins were originally identified as having roles as guidance cues during neural development. Class 3 semaphorins are involved in cancer progression. However, the roles of class 3 semaphorins in hepatocellular carcinoma (HCC) are unknown. We examined the expression levels of class 3 semaphorins in HCC cell lines with different metastatic potential and in carcinoma tissue samples. The results indicated that Semaphorin 3A expression was up-regulated in metastatic cell lines and in samples from patients with tumor recurrence. Cell functional studies revealed that Semaphorin 3A promoted HCC cell proliferation, migration, and invasion. Animal studies indicated that Semaphorin 3A overexpression enhanced tumor growth and lung metastasis. Semaphorin 3A also acted as a chemoattractant involved in direct recruitment of macrophages in vitro, and facilitated tumor-associated macrophage (TAM) infiltration in vivo. Multivariate analysis revealed that Semaphorin 3A expression alone, or combined with the number of TAMs, can be an independent predictor for overall survival time and time to recurrence. Overall, the results suggested that Semaphorin 3A increased TAM infiltration and promoted HCC progression. Semaphorin 3A expression alone, or combined with the number of TAMs, is a new prognostic factor and potential target for the treatment of HCC.

// Er-Bao Chen 1, 2, * , Shao-Lai Zhou 1, * , Xu-Guang Pang 3, * , Dan Yin 1 , Pei-Zhen Miao 1 , Yi Yang 1 , Qing Chen 1 , Kai Zhu 1 , Dong-Mei Gao 1 , Tian-Shu Liu 4 , Xiao-Yi Wang 1 , Ying-Hong Shi 1 , Wei-Zhong Wu 1 , Jian Zhou 1, 2 , Zheng-Jun Zhou 1 and Zhi Dai 1, 2 1 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Labolatory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, China 2 State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China 3 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China 4 Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Zhi Dai, email: dai.zhi@zs-hospital.sh.cn Zheng-Jun Zhou, email: zhou.zhengjun@zs-hospital.sh.cn Keywords: PDEF, HCC, EMT, invasion, proliferation Received: August 25, 2016 Accepted: December 27, 2016 Published: January 31, 2017 ABSTRACT Prostate-derived E-twenty-six (ETS) factor (PDEF), an epithelium-specific ETS transcription factor, regulates carcinogenesis and tumor progression. The prognostic importance and biologic functions in hepatocellular carcinoma (HCC) have not been established. We investigated PDEF expression in 400 HCC patients using quantitative real-time polymerase chain reaction, western blot and immunohistochemistry analysis. PDEF expression was significantly lower in tumors than in peritumoral tissues. Lower PDEF levels were associated with poorer prognosis in patients. PDEF was an independent predictor of overall survival in multivariate analysis. PDEF expression was suppressed in highly metastatic HCC cell lines, and shRNA-mediated down-regulation of PDEF in low-metastatic HCC cell lines (with high PDEF) significantly increased cellular proliferative and invasive capacity in vitro and in vivo . RNA sequencing analysis indicated that PDEF may mediate transcription of several genes involved in apoptosis and the cell cycle. PDEF modulated epithelial-mesenchymal transition by up-regulating E-cadherin expression and down-regulating Slug and Vimentin expression, thereby lowering migration and invasion abilities of HCC cells. In conclusion, PDEF is associated with proliferation and invasiveness of HCC cells. It may serve as an independent predictor of prognosis in patients with HCC.