Down-Regulation Of 4-Hydroxyphenylpyruvate Dioxygenate (Hpd) Contributes To The Pathogenesis Of Hepatocellular Carcinoma (Hcc) Through Erk / Bcl-2 Signalling Activation

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. Metastasis, recurrence and therapy resistance remain major obstacles to the improvement of long-term survival and represent major causative factors contributing to the rising mortality rates and poor prognosis of HCC. Identification of key drivers important for clinical prognostic utility and elucidation of mechanisms involved in hepatocarcinogenesis is urgently needed to aid in the development of novel treatment modalities. To this end, we began our study with an analysis of a publicly gene expression dataset (GSE14520) comprising of transcriptomic profiles from a large cohort of human non-tumor liver and HCC clinical samples in hope to establish a prognostic gene signature associated with metastatic risk / recurrence status so to identify novel driver genes responsible for HCC development and progression. By this method, 4-hydroxyphenylpyruvate dioxygenase (HPD) was identified as a candidate tumor suppressor gene in HCC. HPD was found to be frequently down-regulated in primary HCC tumors as compared with peri-tumor liver tissues. Its expression negatively correlated with aggressive HCC pathological features, including tumor stage, metastasis, recurrence and survival. Notably, down-regulated HPD expression in HCC is in part a result of hypermethylation at the HPD promoter. The functional effect of HPD was then examined in HCC cells with or without HPD stably repressed or ectopically overexpressed. Upon knockdown of HPD, HCC cells displayed significantly enhanced abilities to form tumors, metastasize and confer sorafenib resistance in vitro and in vivo. Conversely, overexpression of HPD in HCC cells led to an opposing effect. Consistently, sorafenib-resistant HCC patient derived xenografts also displayed attenuated levels of HPD as compared with parental sorafenib-sensitive counterparts. Mechanistically, HPD down-regulation mediates aggressive cancer features in HCC through activation of an ERK and BCL-2 pro-survival signaling pathway, as evidenced by rescue experiments involving the ERK inhibitor U0126. Collectively, our findings suggest HPD down-regulation in HCC tumors to promote tumorigenicity, metastasis and sorafenib resistance through ERK / BCL-2 signaling activation and that HPD may represent a novel prognostic biomarker for HCC. Citation Format: Man Tong, Tin Lok Wong, Steve Tin-Chi Luk, Noelia Che, Kai Yau Wong, Tsun Ming Fung, Xin-Yuan Guan, Nikki P Lee, Yun-Fei Yuan, Terence K Lee, Stephanie Ma. Down-regulation of 4-hydroxyphenylpyruvate dioxygenate (HPD) contributes to the pathogenesis of hepatocellular carcinoma (HCC) through ERK / BCL-2 signalling activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1548. doi:10.1158/1538-7445.AM2017-1548