Frequent inactivation of p16INK4a in oral premalignant lesions

Papadimitrakopoulou, Vali; Izzo, Julie; Lippman, Scott M.; Lee, Jin Soo; Fan, You Hong; Clayman, Gary L.; Ro, Jungsil; Hittelman, Walter N.; Lotan, Reuben; Hong, Waun Ki; Mao, Li

doi:10.1038/sj.onc.1201010

Cited by 146 publications

(109 citation statements)

References 19 publications

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“…Overall, these experiments expressing hTERT ectopically in D30/D25 and D17 strongly suggest that telomerase activation/telomere maintenance is not sufficient per se to immortalize naturally occurring mortal dysplasias unless they have lost the expression of RAR-b and/or p16 INK4A . Loss of p16 INK4A and RAR-b in dysplasias is not an in vitro artefact, since both changes have been found in a large fraction of dysplasias in vivo (Xu et al, 1994;Papadimitrakopoulou et al, 1997). In a similar way, recent work sequentially abrogating Rb and p53 responses in human fibroblasts demonstrated extensions in lifespan, but not immortalization (Morris et al, 2002).…”

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confidence: 62%

Senescing oral dysplasias are not immortalized by ectopic expression of hTERT alone without other molecular changes, such as loss of INK4A and/or retinoic acid receptor-β: but p53 mutations are not necessarily required

et al. 2003

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confidence: 62%

Senescing oral dysplasias are not immortalized by ectopic expression of hTERT alone without other molecular changes, such as loss of INK4A and/or retinoic acid receptor-β: but p53 mutations are not necessarily required

et al. 2003

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“…INK4a inactivation is believed to be an early event in oral carcinogenesis (4)(5)(6)(7)(8). Some authors reported that loss of p16…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of p21WAF1/CIP1, p16INK4a and CD44s in tongue cancer

González‐Moles

Gil-Montoya²,

Ruiz‐Ávila³

et al. 2007

Oncol Rep

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Abstract. The role of lost or reduced expression of p21, p16 and CD44s in the survival of tongue cancer patients was investigated. Tumours and adjacent non-tumour epithelia (ANTE) from 36 patients with tongue cancer were retrospectively studied by immunohistochemistry using monoclonal antibodies against p21, p16 and CD44s proteins. Expression of p21, p16 and CD44s and their relationship with clinical and pathological parameters were analyzed. Of 36 patients, 12 (33.33%) developed recurrence and 12 died of the disease (mean survival, 25.5 months). In four cases (11.1%), concomitant low expression (<50% of tumour cells) of p21, p16 and CD44s was detected but had no effect on survival or recurrence in the univariate analysis. In the multivariate analysis, low expression of CD44s was the sole prognostic factor related to survival (p=0.01, hazards ratio: 0.749). There was no expression of p21, p16 or CD44s in ANTE from 3 out of 24 cases studied, and this finding was related to recurrence in the univariate analysis. In the multivariate analysis, low expression of CD44s in ANTE was again the sole factor related to recurrence (p=0.002, hazards ratio: 0.028). In conclusion, low expression of CD44s is related to tumour cell invasiveness and may be of clinical relevance as a prognostic factor. IntroductionCellular programs of proliferation, differentiation, senescence and apoptosis are closely linked to cell cycle regulation, and alterations of the cell cycle machinery have been described as a hallmark of cancer development (1). Molecular mechanisms controlling progression through the restriction point (R), such as the retinoblastoma protein (pRB), are of paramount importance in this context (2). Hypophosphorylated pRB inhibits S phase entry (cell arrest near R point) by forming complexes with E2F transcription factors that actively repress transcription of DNA synthesis-regulating genes (3). Upon pRB phosphorylation, pRB/E2F complexes are disrupted and E2F can activate these promoters, allowing the advance of cells to late G1 and DNA synthesis. Therefore, pRB or members of this regulatory pathway are critical molecular targets for malignant transformation, and there is growing evidence that the pRB pathway is rendered dysfunctional in oral cancer (2). Down-regulation of p16INK4a , a member of the INK family of CDK inhibitors (CDKis), has been described in oral cancer, and p16INK4a inactivation is believed to be an early event in oral carcinogenesis (4-8). Some authors reported that loss of p16INK4a is correlated with a poor prognosis in oral cancer patients (9-11), whereas others found no relationship with survival (12). In addition, some studies found loss of p21 WAF1/CIP1 , a member of CIP/KIP family of CDKis, to be a very early event in oral carcinogenesis (13)(14)(15)(16)(17). However, the prognostic significance of p21 WAF1/CIP1 expression is controversial, with several studies identifying it as a prognostic factor (18-20) and others finding no association (17,(21)(22)(23)(24).Besides alterations in their cell-cycle ...

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“…p16/MTS1 is located on 9p21 in humans, a region commonly deleted in many tumour types (Fountain et al, 1992;Kamb et al 1994). As well as gene deletion (van der Riet et al, 1994;Reed et al, 1996), point mutations (Zhou et al, 1994;Liu et al, 1995;Arap et al, 1997), methylation (Gonzalez-Zulueta et al, 1995;Otterson et al, 1995;Shapiro et al, 1995) and the TAX protein of HTLV1 virus (Suzuki et al, 1996) have been found to inactivate p16/MTS1 in several tumour types including head and neck (Reed et al, 1996;Olshan et al, 1997;Papadimitrakopoulou et al, 1997).…”

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confidence: 99%

Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines

Sartor¹,

Steingrimsdottir²,

El-Amin³

et al. 1999

Br J Cancer

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One of the most important components of G1 checkpoint is the retinoblastoma protein (pRB 110 ). The activity of pRB is regulated by its phosphorylation, which is mediated by genes such as cyclin D1 and p16 / MTS1 . All three genes have been shown to be commonly altered in human malignancies. We have screened a panel of 26 oral squamous cell carcinomas (OSCC), nine premalignant and three normal oral tissue samples as well as eight established OSCC cell lines for mutations in the p16 / MTS1 gene. The expression of p16 / MTS1 , cyclin D1 and pRB 110 was also studied in the same panel. We have found p16 / MTS1 gene alterations in 5/26 (19%) primary tumours and 6/8 (75%) cell lines. Two primary tumours and five OSCC cell lines had p16/MTS1 point mutations and another three primary and one OSCC cell line contained partial gene deletions. Six of seven p16/MTS1 point mutations resulted in termination codons and the remaining mutation caused a frameshift. Western blot analysis showed absence of p16/MTS1 expression in 18/26 (69%) OSCC, 7/9 (78%) premalignant lesions and 8/8 cell lines. One cell line, H314, contained a frameshift mutation possibly resulting in a truncated p16/MTS1 protein. pRB was detected in 14/25 (56%) of OSCC but only 11/14 (78%) of these contained all or some hypophosphorylated (active) pRB. In premalignant samples, 6/8 (75%) displayed pRB, and all three normal samples and eight cell lines analysed contained RB protein. p16/MTS1 protein was undetectable in 10/11 (91%) OSCCs with positive pRB. Overexpression of cyclin D1 was observed in 9/22 (41%) OSCC, 3/9 (33%) premalignant and 8/8 (100%) of OSCC cell lines. Our data suggest p16/MTS1 mutations and loss of expression to be very common in oral cancer cell lines and less frequent in primary OSCC tumours. A different pattern of p16/MTS1 mutations was observed in OSCC compared to other cancers with all the detected p16/MTS1 mutations resulting in premature termination codons or a frameshift. The RB protein was expressed in about half (44%) of OSCCs and its expression inversely correlated with p16/MTS1 expression. In conclusion, we show that abnormalities of the RB pathway are a common mechanism of oral carcinogenesis. © 1999 Cancer Research Campaign

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Frequent inactivation of p16INK4a in oral premalignant lesions

Cited by 146 publications

References 19 publications

Senescing oral dysplasias are not immortalized by ectopic expression of hTERT alone without other molecular changes, such as loss of INK4A and/or retinoic acid receptor-β: but p53 mutations are not necessarily required

Senescing oral dysplasias are not immortalized by ectopic expression of hTERT alone without other molecular changes, such as loss of INK4A and/or retinoic acid receptor-β: but p53 mutations are not necessarily required

Prognostic significance of p21WAF1/CIP1, p16INK4a and CD44s in tongue cancer

Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines

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