Alternative splicing of estrogen receptor alpha in hepatocellular carcinoma

Jian Zhang, Jianwei Ren, Jiamin Wei, Charing C. N. Chong, Dongjie Yang, Yulong He, George G. Chen, Paul B. S. Lai

The role of estrogen receptor alpha (ERa), estrogen receptor beta (ERb) and ERa36 signaling in hepatocellular carcinoma (HCC) is not fully addressed. In this study, three cohorts were included: (i) primary HCC patients (N = 76, cohort P), (ii) colorectal liver metastasis (mCRC) (N = 32, cohort S), and (iii) HCC from The Cancer Genome Atlas (TCGA) (N = 121). The levels of ERa36 and wtER36 were measured and their correlation with clinicopathologic features was determined. WtERa was downregulated and that ERa36 was upregulated in tumor tissues in both cohort P and TCGA data set. ERa36 was downregulated in tumor tissues in cohort S. In cohort P, wtERa was differentially expressed in gender (P < 0.000), age (P = 0.004), tumor number (P = 0.043), tumor size (P = 0.002), intrahepatic recurrence (P = 0.054). ERa36 was unequally expressed in different non-tumor liver status (P = 0.040). WtERa was negatively associated with overall survival (OS) and disease free survival (DFS) in cohort P. Compared with non-tumor tissues, the expression of ERa36 was increased in primary HCC but decreased in secondary HCC, showing opposite expression patterns of ERa36 between primary HCC and secondary HCC. Primary HCC is associated with the decreased WtERa but increased ERa36. The expression pattern of ERa36 is different between primary HCC and secondary HCC, as the former with the increased ERa36 but the latter with the decreased ERa36. Therefore, the expression of ERa36 may be used to differentiate the primary HCC and the secondary one.