WWOX controls hepatic HIF1\u03b1 to suppress hepatocyte proliferation and neoplasia

Muhannad Abu-Remaileh,Abed Khalaileh,Eli Pikarsky,Rami I Aqeilan

doi:10.1038/s41419-018-0510-4

Abstract

Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The WW domain-containing oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC. WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia-inducible factor 1α (HIF-1α) levels and function. Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development. WWOX liver-specific knockout mice (WwoxΔHep) showed more potent liver regeneration potential and enhanced proliferation as compared with their control littermates. Moreover, WWOX deficiency in hepatocytes combined with diethylnitrosamine treatment increased the tumor burden, which was associated with increased HIF1α levels and target gene transactivation. Inhibition of HIF1α by systemic treatment with digoxin significantly delayed HCC formation. Our work suggests that WWOX inactivation has a central role in promoting HCC through rewiring of cellular metabolism and modulating proliferation.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, representing the fifth type of commonly diagnosed cancer worldwide and third mortality cause among other cancer malignances[1]
Using Xena browser we evaluated the prognostic value of WW domain-containing oxidoreductase (WWOX) expression in HCC and found that cases harboring reduced WWOX mRNA levels tend to present with worse survival outcome compared to those having high WWOX expression (Fig. 1b)
Consistent with these observations we further found that WWOX levels are absent or reduced in different liver pathologies, in HCC, as assessed by immunohistochemical staining of a commercial tissue microarray (Fig. 1c, d)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, representing the fifth type of commonly diagnosed cancer worldwide and third mortality cause among other cancer malignances[1]. HCC prevalence has been dramatically increasing in the last decay because of the expansion of HCC risk factors, including hepatitis infection and obesity[2]. Therapeutic options are limited and survival after diagnosis is still poor leading to high mortality. Better understanding of the molecular basis of HCC is urgently needed. WW domain-containing oxidoreducatase (WWOX) gene resides in one of the most common fragile sites known as FRA16D, a region that is altered in many types of cancer[3,4,5].

Methods

Results

Conclusion