An immunohistochemical study of p16INK4a expression in multistep thyroid tumourigenesis

Ball, Elizabeth; Bond, Jane A.; Franc, Brigitte; DeMicco, Catherine; Wynford-Thomas, David

doi:10.1016/j.ejca.2006.08.025

Cited by 19 publications

(16 citation statements)

References 30 publications

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“…INK4a in adenomas, papillary and follicular tumours, and the loss of expression in ATC was observed in previous works (Ferru et al 2006, Ball et al 2007, suggesting that p16…”

Section: Ink4amentioning

confidence: 86%

Evidence of oncogene-induced senescence in thyroid carcinogenesis

Vizioli

Possik

Tarantino

et al. 2011

Endocrine-Related Cancer

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Oncogene-induced senescence (OIS) is a growth arrest triggered by the enforced expression of cancer-promoting genes and acts as a barrier against malignant transformation in vivo. In this study, by a combination of in vitro and in vivo approaches, we investigate the role of OIS in tumours originating from the thyroid epithelium. We found that expression of different thyroid tumour-associated oncogenes in primary human thyrocytes triggers senescence, as demonstrated by the presence of OIS hallmarks: changes in cell morphology, accumulation of SA-b-Gal and senescence-associated heterochromatic foci, and upregulation of transcription of the cyclindependent kinase inhibitors p16INK4a and p21 CIP1 . Furthermore, immunohistochemical analysis of a panel of thyroid tumours characterised by different aggressiveness showed that the expression of OIS markers such as p16 INK4a, p21 CIP1 and IGFBP7 is upregulated at early stages, and lost during thyroid tumour progression. Taken together, our results suggest a role of OIS in thyroid carcinogenesis.

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“…INK4a in adenomas, papillary and follicular tumours, and the loss of expression in ATC was observed in previous works (Ferru et al 2006, Ball et al 2007, suggesting that p16…”

Section: Ink4amentioning

confidence: 86%

Evidence of oncogene-induced senescence in thyroid carcinogenesis

Vizioli

Possik

Tarantino

et al. 2011

Endocrine-Related Cancer

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“…Although it is possible that p14/p16 up-regulation represents a thyrocyte's attempt to counter the hyperproliferative signals generated by Kras and PI3K, additional studies are warranted to fully understand this finding. Nonetheless, it is worthy of note that CDKN2A up-regulation has been frequently reported in thyroid carcinomas (26-28). …”

Section: Discussionmentioning

confidence: 97%

Oncogenic Kras Requires Simultaneous PI3K Signaling to Induce ERK Activation and Transform Thyroid Epithelial Cells In vivo

et al. 2009

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Thyroid tumors arising from the follicular cells often harbor mutations leading to the constitutive activation of the PI3K and Ras signaling cascades. However, it is still unclear what their respective contribution to the neoplastic process is, as well as to what extent they interact. We have used mice harboring a Kras oncogenic mutation and a Pten deletion targeted to the thyroid epithelium to address in vivo these questions. Here, we show that although each of these two pathways, alone, is unable to transform thyroid follicular cells, their simultaneous activation is highly oncogenic, leading to invasive and metastatic follicular carcinomas. In particular, phosphatidylinositol-3-kinase (PI3K) activation suppressed Kras-initiated feedback signals that uncouple mitogenactivated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activation, thus stunting MAPK activity; in addition, PI3K and Kras cooperated to drastically up-regulate cyclin D1 mRNA levels. Finally, combined pharmacologic inhibition of PI3K and MAPK completely inhibited the growth of double-mutant cancer cell lines, providing a compelling rationale for the dual targeting of these pathways in thyroid cancer. [Cancer Res 2009;69(8):3689-94]

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“…Recently, some authors have investigated p16 ink4a expression by immunohistochemistry [27][28][29][30][31]. Most of the reports have found a high expression in PTC, but its clinical significance remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Expression of p21cip1, p27kip1, and p16INk4a Cyclin-Dependent Kinase Inhibitors in Papillary Thyroid Carcinoma: Correlation with Clinicopathological Factors

Zafón

Obiols

Castellví³

et al. 2008

Endocr Pathol

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In a variety of human malignancies, aberrant expression of proteins involved in the control of cell-cycle progression has been reported. In this study, p21cip1, p27kip1, and p16INk4a cyclin-dependent kinase inhibitors were analyzed to evaluate their usefulness in clinical management of papillary thyroid carcinoma (PTC). Archived material derived from 46 cases of PTC was analyzed immunohistochemically. Protein expression was ascertained on tissue microarrays, and results were correlated with clinicopathological features of the patients. Positive immunostaining was observed in 14 (30,4%) p21cip1, 26 (56,5%) p27kip1, and 14 (30,4%) p16INk4a cases. No significant correlation between p21cip1 or p27kip1 and clinical factors was found. In contrast, p16INk4a expression showed a significant correlation with initial extension of the disease. Therefore, 45.8% of patients with loco-regional extension were p16INk4a positive, whereas overexpression was only seen in 15.7% of cases with intrathyroid disease (p < 0.05). Moreover, all patients with simultaneous p16INk4a positivity and lack of p27kip1 staining (four patients) presented lymph node metastases. In contrast, only 12 (28.5%) of the remaining patients showed lymph node tumor involvement. In conclusion, p16INk4a expression suggests extrathyroid neck extension of PTC. This effect is enhanced when p27kip1 is negative. We think that their analysis by immunohistochemistry could be useful in the management of patients with PTC.

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An immunohistochemical study of p16INK4a expression in multistep thyroid tumourigenesis

Cited by 19 publications

References 30 publications

Evidence of oncogene-induced senescence in thyroid carcinogenesis

Evidence of oncogene-induced senescence in thyroid carcinogenesis

Oncogenic Kras Requires Simultaneous PI3K Signaling to Induce ERK Activation and Transform Thyroid Epithelial Cells In vivo

Expression of p21cip1, p27kip1, and p16INk4a Cyclin-Dependent Kinase Inhibitors in Papillary Thyroid Carcinoma: Correlation with Clinicopathological Factors

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