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

Xiangjun Kong,Mingming Wu,Weijie Zhang,Yijun Chen,Min Zhang,Vijay Pandey,Pengxu Qian,Tao Zhu,Zhengsheng Wu,Xuefei Lu,Gaopeng Li,Peter E Lobie,Jo K Perry,Wenyong Wu,Yan Yuan,Sheng Tan

doi:10.18632/oncotarget.8781

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.

Highlights

In addition to their classic endocrine actions, human growth hormone and human prolactin have been reported to function as autocrine and/or paracrine growth factors in tissues such as the mammary gland, endometrium, prostate and central nervous system including the retina [1]
This study has demonstrated a significant association of tumor human growth hormone (hGH) expression with clinicopathological characteristics of hepatocellular carcinoma (HCC)
We observed no significant association of tumor human prolactin (hPRL) expression with any clinicopathological features of HCC, both hGH and hPRL expression were individually associated with poor survival of HCC patients overall and www.impactjournals.com/oncotarget in male HCC patients

Summary

Introduction

In addition to their classic endocrine actions, human growth hormone (hGH) and human prolactin (hPRL) have been reported to function as autocrine and/or paracrine growth factors in tissues such as the mammary gland, endometrium, prostate and central nervous system including the retina [1]. Independent of serum hGH, hPRL or IGF1 levels, expression of hGH or hPRL in mammary or endometrial carcinoma is associated with unfavorable histopathological features with a significantly worse survival outcome for patients [8]. Both hGH and hPRL exert tissue and disease specific functions in an autocrine/paracrine manner. Both the GH receptor and PRL receptor were first identified and characterized in liver [9, 10]. Several investigations identified that serum PRL levels were significant elevated in HCC patients and PRL was one of the potential tumor markers for HCC, suggesting that hPRL may be useful as a biomarker for early detection of HCC and may play a role in HCC progression [21,22,23]

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Conclusion