p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

Abstract

p16 Ink4a is a protein involved in regulation of the cell cycle. Currently, p16 Ink4a is considered a tumor suppressor protein because of its physiological role and downregulated expression in a large number of tumors. Intriguingly, overexpression of p16 Ink4a has also been described in several tumors. This review attempts to elucidate when and why p16 Ink4a overexpression occurs, and to suggest possible implications of p16 Ink4a in the diagnosis, prognosis and treatment of cancer.

The Cyclin-dependent Kinase Inhibitor p16INK4a Physically Interacts with Transcription Factor Sp1 and Cyclin-dependent Kinase 4 to Transactivate MicroRNA-141 and MicroRNA-146b-5p Spontaneously and in Response to Ultraviolet Light-induced DNA Damage

“…Indeed, CDKN2A is a master tumor suppressor gene that has been found mutated or silenced in various types of neoplasms, and the inactivation of this gene is among the most frequent and earliest cytogenetic events in human cancer (11,41). Furthermore, p16 overexpression has also been found in some benign tumors and in some cancer types, such as cervical cancer, breast cancer, and head and neck cancer (13,14). Sp1, which is the major transcription factor in the complex, is involved in the transcription of many genes implicated in most cellular processes.…”

“…CDKN2A is an important tumor suppressor gene, which is frequently inactivated by point mutations, promoter methylation, or deletion in various types of human cancer (11,12). Additionally, several lines of evidence indicate that p16 is overexpressed at both protein and mRNA levels in certain tumors, and this has been shown to be associated with poor prognosis (13,14). Furthermore, it became clear that p16 interacts with several proteins (15,16), and it also regulates the expression of different genes involved in various cellular processes (17,18).…”

A diagnostic algorithm for atypical spitzoid tumors: guidelines for immunohistochemical and molecular assessment

“…16,17 p16 Ink4a is a cyclin-dependent kinase inhibitor that blocks formation of the catalytically active CDK4/6-cyclin D complex, thereby preventing the phosphorylation of the retinoblastoma (Rb) gene and passage through the cell cycle's G1/S checkpoint (Figure 2a). [17][18][19][20] As a tumor suppressor, p16 is found in low levels in normal proliferating cells but events such as DNA damage, oncogenic stress, and aging trigger its Figure 1 Four scenarios from the proposed diagnostic algorithm for the assessment of the malignant potential of atypical spitzoid tumors. In addition to classical morphological evaluation, this algorithm applies a set of immunohistochemical assays (a dual-color of Ki67/ MART-1 (Leica Biosystems), p16 Ink4a (Roche Life Sciences), and HMB45 (Leica Biosystems)), a fluorescence in situ hybridization (FISH) with five probes (6p25, 8q24, 11q13, centromere 9, and 9p21; NeoSITE melanoma, Neogenomics Laboratories), and an array-based comparative genomic hybridization (aCGH) assay (University of California, San Francisco).…”

“…17,20 The tumor suppressors p14 ARF and p16 INK4A are coded from alternatively spliced transcripts in different reading frames at the INK4A/ARF locus on chromosome 9p21 (Figure 2a). The INK4A/ ARF locus on chromosome 9p21 is frequently altered in human cancer, and inherited p16 Ink4a /p14 ARF mutations are associated with melanoma susceptibility in 20-40% of familial melanomas.…”

“…In benign melanocytic nevi expressing the BRAF V600E mutation, overexpression of p16 has been observed and probably contributes to senescence and a state of arrested growth. 20 Figure 2d illustrates one example of an intradermal nevus clearly demonstrating dense homogeneous expression of p16, whereas a homogeneous loss of p16 is observed in the invasive melanoma.…”