Abstract
Pre-mRNA alternative splicing is an essential step in the process of gene expression. It provides cells with the opportunity to create various protein isoforms. Disruptions of alternative splicing are associated with various diseases, including cancer. The muscleblind-like (MBNL) protein is a splicing regulatory protein. Overexpression of MBNL proteins in embryonic stem cells promotes differentiated cell-like alternative splicing patterns. We examined the expression level of MBNL2 in 143 resected HCCs using immunohistochemistry. MBNL2 was overexpressed in 51 (35.7%) HCCs. The overexpression of MBNL2 correlated with smaller tumor size (≤ 3 cm, P = 0.0108) and low tumor stage (Stage I, P = 0.0026), indicating that MBNL2 expression was lost in the late stage of HCC development. Furthermore, patients with MBNL2-positive HCCs had a borderline better 5-year overall survival (P = 0.0579). In non-cancerous liver parenchyma, MBNL2 was stained on the Canals of Hering and hepatocytes newly derived from hepatic progenitor cells. The overexpression of MBNL2 in Hep-J5 cells suppressed proliferation, tumorsphere formation, migration, and in vitro invasion, and also reduced in vivo tumor growth in NOD/SCID mice. In contrast, MBNL2 depletion with RNA interference in Huh7 cells increased in vitro migration and invasion, but did not enhance tumor growth. These results indicate that MBNL2 is a tumor suppressor in hepatocarcinogenesis.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide, in Taiwan, Southern China, Southeast Asia, and subSaharan Africa
We found that MBNL2 was colocalized with EpCAM in non-cancerous liver parenchyma (Figure 3A), indicating that MBNL2 was expressed in hepatocytes newly derived from hepatic progenitor cells
The role of MBNL proteins in alternative splicing in ES cells was reported by Han et al [25]
Summary
Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide, in Taiwan, Southern China, Southeast Asia, and subSaharan Africa. The major risk factors are hepatitis B and C infections, cirrhosis, and exposure to environmental carcinogens such as aflatoxins [1]. Molecular studies have revealed the involvement of p53 and β-catenin mutations in hepatocarcinogenesis [2, 3]. The molecular mechanisms of HCC remain largely unclear. Most HCC cases are treated with locoregional therapy modalities such as surgical resection, transarterial chemoembolization, and radiofrequency ablation. Sorafenib is the only available effective systemic therapy, which provides an approximate
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