MicroRNA-22 is down-regulated in hepatitis B virus-related hepatocellular carcinoma

Abstract

MicroRNAs (miRNAs) are a new class of short noncoding RNAs with post-transcriptional regulation and participate in diverse physiological and pathological processes. MiR-22, ubiquitously expressed in various tissues, plays a functional important role in life processes and is recently proved to involve in many cancers. In present study, we had shown that miR-22 was down-regulated much more obviously in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) cell lines as well as in clinical tissues. Cyclin-dependent kinase inhibitor 1A (CDKN1A) was found to be inversely correlated with miR-22 and was identified as a target of miR-22. Overexpression of miR-22 in vitro effectively suppressed CDKN1A expression and inhibited cell proliferation. We conclude that miR-29c may play an important role as a tumor suppressive microRNA in the development and progression of HBV-related HCC by targeting CDKN1A.

Introduction

Hepatocellular carcinoma (HCC) is the third aggressive cancers in the world and the second in China [1]. It has demonstrated that hepatitis B virus (HBV) infection is one of the key risk factors for HCC [2], which is greatly detrimental to human health and affects the quality of people's life [3]. China, a country of high prevalence of HBV infection, has about 12 million chronic HBV carriers and approximately 30 million chronic hepatitis B patients. Furthermore, the number increasing with a rate of (10 ~ 25) × 10⁵ cases every year [4]. Therefore, it is of great importance to investigate the pathogenesis of HBV infection as well as the carcinogenesis of HBV-related HCC. The discovery of miRNAs brings new possibility for devising new strategies for its prevention and therapy.

MicroRNAs (miRNAs) are a new class of small noncoding RNAs that may bind to the imperfect complementary sequences of their target mRNAs at the 3′ untranslated regions (3′-UTR) and induce mRNA degradation or translational repression [5]. MiRNAs have been shown to regulate gene expression in complicated physiological and pathological processes [6], such as development, proliferation, apoptosis, stress responses and so on [7]. Recent studies have found that aberrant miRNA expression is closely associated with a number of disease and cancer [8], [9]. Moreover, a large number of studies have proved that miRNA expression is nearly ubiquitous deregulation in different cancer cells [10], [11]. In addition, a growing number of studies has documented that altered expression of specific miRNAs contribute to tumorigenesis and miRNAs may act as tumor suppressors or oncogenes [12], [13], [14].

MiR-22 was originally detected in HeLa cells, but was later found to be ubiquitously expressed in various tissues [15]. The gene encoding miR-22 is found on the short arm of chromosome 17, and is highly conserved across many vertebrate species, including chimp, mouse, rat, dog and horse. This level of conservation suggests that miR-22 play a functional important role in life processes. Recently, more and more studies have found that miR-22 was down-regulated in many cancers, including cholangiocarcinoma, multiple myeloma and hepatocellular carcinoma [16]. In HBV-related HCC, the role of miR-22 remains largely unknown.

Here, we investigated whether miR-22 could have a role in HBV-related HCC. We found that miR-22 was s expressed relatively weakly in HBV-related HCC cell lines and in HBV clinical specimens compared with their corresponding controls. CDKN1A, as a target gene of miR-22, was found to be inversely correlated with miR-22 levels both in cell lines and in clinical specimens. We also moreover demonstrated that the overexpression of miR-22 in HepG2.2.15 cells effectively suppressed CDKN1A expression and cell proliferation. In this study, we report that miR-22 regulates cell proliferation by targeting CDKN1A in HBV-related cell lines, showing that miR-22, as a tumor suppressor miRNA, may play an important role in the development of HBV-related HCC.