Aberrant expression of p16INK4a in human cancers – a new biomarker?

Kazushi Inoue,Elizabeth A Fry

doi:10.15761/crr.1000145

Abstract

The ARF and INK4a genes are located in the same CDKN2a locus, both showing its tumor suppressive activity. ARF has been shown to detect potentially harmful oncogenic signals, making incipient cancer cells undergo senescence or apoptosis. INK4a, on the other hand, responds to signals from aging in a variety of tissues including islets of Langerhans, neuronal cells, and cancer stem cells in general. It also detects oncogenic signals from incipient cancer cells to induce them senescent to prevent neoplastic transformation. Both of these genes are inactivated by gene deletion, promoter methylation, frame shift, and aberrant splicing although mutations changing the amino acid sequences affect only the latter. Recent studies indicated that polycomb gene products EZH2 and BMI1 repressed p16INK4a expression in primary cells, but not in cells deficient for pRB protein function. It was also reported that that p14ARF inhibits the stability of the p16INK4a protein in human cancer cell lines and mouse embryonic fibroblasts through its interaction with regenerating islet-derived protein 3γ. Overexpression of INK4a is associated with better prognosis of cancer when it is associated with human papilloma virus infection. However, it has a worse prognostic value in other tumors since it is an indicator of pRB loss. The p16INK4a tumor suppressive protein can thus be used as a biomarker to detect early stage cancer cells as well as advanced tumor cells with pRB inactivation since it is not expressed in normal cells.

Highlights

Since the discovery as a product of the alternate reading frame of the mouse Arf/Ink4a locus signals, the Arf tumor suppressor has been identified as a key sensor of hyperproliferative stimuli such as those originating from oncoproteins to prevent early stage cancer cells undergo neoplastic transformation by inducing senescence or apoptosis [1,2]. p19Arf and p16Ink4a are transcribed from separate and unique first exons 1β and 1α which splice into two shared exons 2 and 3 (Figure 1)
Several pieces of evidence suggested that the ability to bypass senescence is the main molecular mechanism in the progression of pre-malignant to fully malignant cells [58,59]. This hypothesis is based on the concept of oncogene-induced senescence (OIS), which was established after demonstration of p53- and p16Ink4a-mediated senescent-like growth arrest in response to expression of oncogenic Ras in normal primary cells [18,58,59,60], which has been considered as highly possible mechanism to prevent proliferation of incipient cancer cells
Since p16Ink4a is involved in OIS, the overexpression has been found in benign and pre-malignant lesions with senescent cells where the ARF/INK4a locus plays its role [61,62,63]

Summary

Introduction

Since the discovery as a product of the alternate reading frame of the mouse Arf/Ink4a locus signals, the Arf tumor suppressor has been identified as a key sensor of hyperproliferative stimuli such as those originating from oncoproteins to prevent early stage cancer cells undergo neoplastic transformation by inducing senescence or apoptosis [1,2]. p19Arf and p16Ink4a are transcribed from separate and unique first exons 1β and 1α which splice into two shared exons 2 and 3 (Figure 1). Consistent with the findings in mice, frequent mutation, promoter methylation, or deletion of the ARF/INK4a locus in human cancers has been reported [5,12,13] second only to p53 in frequency.

Results

Conclusion