Human growth hormone and human prolactin function as autocrine/paracrine promoters of progression of hepatocellular carcinoma

// Xiangjun Kong 1, 2, * , Wenyong Wu 3, * , Yan Yuan 1, 2 , Vijay Pandey 4 , Zhengsheng Wu 5 , Xuefei Lu 1, 2 , Weijie Zhang 1, 2 , Yijun Chen 4 , Mingming Wu 1, 2 , Min Zhang 1, 2 , Gaopeng Li 1, 2 , Sheng Tan 1, 2 , Pengxu Qian 1, 2 , Jo K. Perry 6 , Peter E. Lobie 4, 7 , Tao Zhu 1, 2 1 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China 2 Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China 3 Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China 4 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 5 Department of Pathology, Anhui Medical University, Hefei, Anhui, China 6 Liggins Institute, University of Auckland, Auckland, New Zealand 7 National University Cancer Institute of Singapore, National University Health System, Singapore * These authors have contributed equally to this work Correspondence to: Tao Zhu, e-mail: zhut@ustc.edu.cn Peter E. Lobie, e-mail: csipel@nus.edu.sg Keywords: growth hormone, prolactin, hepatocellular carcinoma, oncogenicity, survival Received: May 19, 2015     Accepted: March 24, 2016     Published: April 18, 2016 ABSTRACT The death rates of hepatocellular carcinoma (HCC) are extremely high due to the paucity of therapeutic options. Animal models and anecdotal clinical evidence indicate a potential role of hGH and hPRL in HCC. However, the prognostic relevance and the functional role of tumor expression of these hormones in human HCC are not defined. Herein, we analyzed the mRNA and protein expression of hGH and hPRL in histopathological samples of non-neoplastic liver and HCC by in situ hybridization, PCR and immunohistochemistry techniques. Increased mRNA and protein expression of both hormones was observed in HCC compared with non-neoplastic liver tissues. hGH expression was significantly associated with tumor size and tumor grade. No significant association was observed between the expression of hPRL and any histopathological features. Amplification of both hGH and hPRL genes in HCC was observed when compared to non-neoplastic tissue. Expression of both hGH and hPRL was associated with worse relapse-free and overall survival in HCC patients. In vitro and in vivo functional assays performed with HCC cell lines demonstrated that autocrine expression of hGH or hPRL in HCC cells increased STAT3 activation, oncogenicity and tumor growth while functional antagonism with hGH-G120R significantly reduced these parameters. Hence, tumor expression of hGH/hPRL is associated with a worse survival outcome for patients with HCC and hGH/hPRL function as autocrine/paracrine promoters of HCC progression.