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

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.

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…The p16 INK4a cyclin-dependent kinase inhibitor (CDKN2a) has been implicated in replicative senescence, the state of permanent growth arrest driven by cell divisions or constitutive Ras-Raf-MEK signaling (see 131–134 for p16 INK4a reviews; Fig. 2).…”

“…The p16 INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest caused by cumulative cell divisions or constitutive Ras-Raf-MEK signaling (50). p16 INK4a is an essential tumor suppressor that prevents the emergence of incipient cancer cells (134). The gene expression is regulated at the transcription level and thus the promoter analysis is critical (135, 136).…”

TP53 mutations and relevance of expression of TP53 pathway genes in paediatric acute myeloid leukaemia

“…For all these genes, except ZMAT3, high expression was associated with inferior OS (Fig 1B, C and Figure S1). Functional annotation of these genes revealed that MDM2 is a direct negative regulator of TP53; CDKN2A encodes for p16 and p14arf, both tumour suppressor proteins regulating cell cycle (Inoue & Fry, 2018); GTSE1 is a protein regulating apoptotic signalling and cell migration and is associated with chemotherapy resistance (Guo et al, 2016); ZMAT3 encodes a protein containing three zinc finger domains and has been shown to inhibit tumour cell growth when overexpressed (Guo et al, 2011); RRM2B, or p53R2, encodes an enzyme named ribonucleotide reductase regulatory TP53 inducible subunit M2B, responsible for generating nucleotide precursors required for DNA replication and is essential for normal DNA repair (Yamaguchi et al, 2001). Although correction of p-values for multiple testing resulted in loss of statistical significance of all genes except GTSE1, we evaluated all five genes for clinical significance.…”

Cervical cancer risk profiling: molecular biomarkers predicting the outcome of hrHPV infection

“…Because of this pathway, p16 dysregulation has been correlated to many malignancies, including cervical cancer. Eventually, E7 mediates the modification of host histone architecture; among these, p16 promoter will also be activated, causing an even higher expression of the protein [119][120][121]. On the other hand, patients with cervical cancer have less expression of p16 due to hypermethylation of its promoter, leading to unsuccessful suppression of tumor growth, and therefore allowing cancer When a cell has to go through G1/S transition, the cyclin-dependent kinases 4 and 6 (CDK4/6) forms a complex with cyclin D. The entire complex phosphorylates the retinoblastoma protein (pRb), which, in normal conditions, binds the transcription factor E2F.…”