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p16 ink4a

Xiyuan Zhang, Guanying Bianca Xu, Dan Zhou, Yuan-Xiang Pan
Background: Liver is the crucial organ as a hub for metabolic reactions. p16(INK4a) is a well-established cyclin-dependent kinase (CDK) inhibitor that plays important role in the molecular pathways of senescence, which lead to irreversible cell cycle arrest with secretion of proinflammatory cytokines and mitochondrial dysfunction. This study tested the hypothesis that cellular senescence regulated by p16(INK4a) is associated with high-fat diet in adult male rats. Methods: Sprague Dawley rats were fed a high-fat (HF) diet or a control (C) diet for 9 weeks after weaning...
2018: Genes & Nutrition
Yapin Su, Jiuwei Cui, Dongsheng Xu, Mengmeng Wang, Tiankai Xu, Huimn Tian, Fujun Han
BACKGROUND: We conducted a systematic review and meta-analysis to investigate the impact of p16(INK4a) status on survival benefits in head and neck squamous cell cancer (HNSCC) after anti-epidermal growth factor receptor (EGFR) based treatments. METHODS: We identified studies assessing anti-EGFR based versus non-anti-EGFR based regimens in patients with unresectable locoregionally advanced, recurrent or metastatic HNSCC. The primary endpoint was progression-free survival (PFS)...
April 2018: Critical Reviews in Oncology/hematology
Sheetal Chauhan, Seema Sen, Anjana Sharma, Seema Kashyap, Radhika Tandon, Mandeep S Bajaj, Neelam Pushker, Murugesan Vanathi, Shyam S Chauhan
AIMS: To evaluate the expression and methylation status of the p16INK4a gene in early and advanced American Joint Committee on Cancer (AJCC) stages of ocular surface squamous neoplasia (OSSN) and to correlate its association with clinicopathological features and survival. METHODS: Sixty-four (35 early and 29 advanced AJCC stage) patients with OSSN formed part of this study and were followed up for 36-58 (mean 48±3.6) months. Immunohistochemical expression of the p16INK4a protein and methylation status of the p16INK4a gene were determined by methylation-specific PCR...
March 6, 2018: British Journal of Ophthalmology
Marisa Mena, Miren Taberna, Sara Tous, Sandra Marquez, Omar Clavero, Beatriz Quiros, Belen Lloveras, Maria Alejo, Xavier Leon, Miquel Quer, Silvia Bagué, Ricard Mesia, Julio Nogués, Montserrat Gomà, Anton Aguila, Teresa Bonfill, Carmen Blazquez, Marta Guix, Rafael Hijano, Montserrat Torres, Dana Holzinger, Michael Pawlita, Miguel Angel Pavon, Ignacio G Bravo, Silvia de Sanjosé, Francesc Xavier Bosch, Laia Alemany
BACKGROUND: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. METHODS: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16INK4a /pRb/p53/Cyclin-D1 immunohistochemistry...
March 2018: Oral Oncology
Jaskaren Kohli, Judith Campisi, Marco Demaria
p16Ink4a is a potent cell cycle inhibitor engaged to support cell cycle arrest during cellular senescence. However, in tumors carrying mutations in key downstream effectors, p16Ink4a is highly expressed but fails to block cell proliferation. p16Ink4a -overexpressing tumor cells are highly aggressive and no targeted interventions are available. To study the effect of specific therapies, we generated murine sarcomas by overexpressing RAS oncogene and disrupting p53 activity. We observed that p16Ink4a -overxpressing murine sarcoma cells were resistant to ABT-263 and ABT-737, anti-cancer small molecules previously shown to eliminate p16Ink4a+ senescent cells...
January 26, 2018: Oncotarget
Xiangrui Li, Zhijian Zhang, Yao Zhang, Yuxiang Cao, Huijun Wei, Zhihao Wu
BACKGROUND: The preferential use of aerobic glycolysis by tumor cells lead to high accumulation of lactate in tumor microenvironment. Clinical evidence has linked elevated lactate concentration with cancer outcomes. However, the role and molecular mechanisms of lactate in cellular senescence and tumor progression remain elusive. METHODS: The function of Snail in lactate-induced EMT in lung cancer cells was explored by wound healing assay and cell invasion assay...
February 26, 2018: Journal of Experimental & Clinical Cancer Research: CR
Jacob T Jackson, Ashley P Ng, Benjamin J Shields, Sue Haupt, Ygal Haupt, Matthew P McCormack
The hematopoietically expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16 Ink4a and p19 Arf However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors...
February 27, 2018: Blood Advances
Isaac K Sundar, Kahkashan Rashid, Janice Gerloff, Dongmei Li, Irfan Rahman
Cigarette smoke (CS) affects DNA damage and cellular senescence signaling pathways in the pathogenesis of chronic obstructive pulmonary disease (COPD). p16(INK4a) (p16: a cyclin-dependent kinase inhibitor) is a key marker of cellular senescence, which is induced by CS in lung cells. It is thought that removal of p16 attenuates premature aging by removing senesced cells. However, the role of p16 in CS-induced stress induce premature senescence (SIPS) and senescence-associated secretory phenotype (SASP during the development of COPD/emphysema is not known...
February 15, 2018: American Journal of Respiratory Cell and Molecular Biology
Xiang Qi, Kevin Tak-Pan Ng, Qizhou Lian, Chang Xian Li, Wei Geng, Chang Chun Ling, Wai Ho Yeung, Yuen Yuen Ma, Xiao Bing Liu, Hui Liu, Jiang Liu, Xin Xiang Yang, Chung Mau Lo, Kwan Man
Background and Aims: Down-regulation of GPx3 accelerated hepatic senescence, which further caused overwhelming inflammation and severe liver graft injury. MSCs derived from human induced pluripotent stem cells (hiPSC-MSCs) have been developed as more efficient delivery vehicle with the property of injury tropism. Here, we aimed to explore the suppressive role of GPx3 in hepatic IR injury using novel delivery system of hiPSC-MSCs. Methods: The mice IR injury model with partial hepatectomy was established. The engineered hiPSC-MSCs delivering GPx3 was constructed...
2018: Theranostics
Atsushi Okuma, Aki Hanyu, Sugiko Watanabe, Eiji Hara
p16Ink4a and p21Cip1/Waf1 act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16Ink4 and p21Cip1/Waf1 , namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16Ink4 and p21Cip1/Waf1 are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3...
December 12, 2017: Nature Communications
Timo Carpén, Anni Sjöblom, Marie Lundberg, Caj Haglund, Antti Markkola, Stina Syrjänen, Jussi Tarkkanen, Antti Mäkitie, Jaana Hagström, Petri Mattila
OBJECTIVES: Oropharyngeal squamous cell carcinoma (OPSCC) is divided in two different disease entities depending on HPV involvement. We investigated differences in presenting symptoms and clinical findings in patients with HPV-positive and -negative OPSCC tumors. METHODS: Altogether 118 consecutive patients diagnosed with primary OPSCC between 2012 and 2014 at the Helsinki University Hospital were included. HPV-status of the tumors was assessed by PCR detection of HPV DNA and immunostaining with p16-INK4a antibody...
November 21, 2017: Acta Oto-laryngologica
Lea Schroeder, Gunnar Wichmann, Maria Willner, Angelika Michel, Manuel Wiesenfarth, Christa Flechtenmacher, Tanja Gradistanac, Michael Pawlita, Andreas Dietz, Tim Waterboer, Dana Holzinger
Treatment of patients with neck lymph node metastasis of squamous cell carcinoma (SCC) from unknown primary tumor (NSCCUP) is challenging due to the risk of missing occult tumors or inducing toxicity to unaffected sites. Human papillomavirus (HPV) is a promising biomarker given its causal link to oropharyngeal SCC and superior survival of patients with HPV-driven oropharyngeal SCC and NSCCUP. Identification of HPV-driven NSCCUP could focus diagnostic work-up and treatment on the oropharynx. For the first time, we assessed HPV antibodies and their prognostic value in NSCCUP patients...
April 1, 2018: International Journal of Cancer. Journal International du Cancer
Guiyan Xu, Jian Yi Li
Glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET) is a rare variant of glioblastoma, which was renamed as glioblastoma with a primitive neuronal component (GBM-PN) in new WHO classification of tumours of the central nervous system in 2016. There are few publications on the investigation of GBM-PN. In this study, PCR mRNA arrays on 6 cases of conventional GBM and 10 cases of GBM-PN showed high mRNA level of CDK4 in GBM-PN and low mRNA level of EGFR in GBM-PN. Immunohistochemical stains on tissue microarrays with 28 cases of conventional GBM and 13 cases of GBM-PN demonstrated that CDK4 was selectively expressed in the primitive neuronal component of all GBM-PN cases while EGFR was positive in conventional GBM and glial component of GBM-PN, but was negative in the primitive neuronal component of all GBM-PN cases...
November 17, 2017: Journal of Neuro-oncology
Marieke Aarts, Athena Georgilis, Meryam Beniazza, Patrizia Beolchi, Ana Banito, Thomas Carroll, Marizela Kulisic, Daniel F Kaemena, Gopuraja Dharmalingam, Nadine Martin, Wolf Reik, Johannes Zuber, Keisuke Kaji, Tamir Chandra, Jesús Gil
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates...
October 15, 2017: Genes & Development
Hai-Rui Wang, Yu-Cong Li, Hui-Qin Guo, Lu-Lu Yu, Zeni Wu, Jian Yin, Guang-Dong Liao, Yi-Min Qu, Yu Jiang, Dong Wang, Wen Chen
Most human papillomavirus (HPV) infections are transient and additional triage approaches should be built after HPV-based primary cervical cancer screening. We evaluated the accuracy of p16/Ki-67 and p16/mcm2 dual staining as biomarkers for triaging HPV positive women in China. 4070 participants aged 35 to 64 years attending ongoing cervical cancer screening were enrolled in 2015-2016. Cervical exfoliated cells were collected for HPV DNA analysis and the residual positive specimens were tested for liquid-based cytology and biomarkers...
October 13, 2017: Oncotarget
Zhi-Hui He, Yan Chen, Ping Chen, Sheng-Dong He, Hui-Hui Zeng, Ji-Ru Ye, Da Liu, Jun Cao
Background: There is a growing realization that COPD, or at least emphysema, involves several processes presenting in aging and cellular senescence. Endothelial progenitor cells (EPCs) contribute to neovascularization and play an important role in the development of COPD. The gene for p16(Ink4a) is a major dominant senescence one. The aim of the present study was to observe changes in lung function, histomorphology of lung tissue, and expression of p16(Ink4a) in lung tissue and bone marrow-derived EPCs in emphysematous mice induced by cigarette-smoke extract (CSE), and further to search for a potential candidate agent protecting against emphysema induced by CSE...
2017: International Journal of Chronic Obstructive Pulmonary Disease
Koji Nakade, Chang-Shen Lin, Xiao-Yu Chen, Ming-Ho Tsai, Kenly Wuputra, Zhi-Wei Zhu, Jian-Zhi Pan, Kazunari K Yokoyama
The main regulators of replicative senescence in mice are p16Ink4a and Arf, inhibitors of cell cycle progression. Jun dimerization protein 2 (JDP2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence through recruitment of the Polycomb repressive complexes 1 and 2 to the promoter of the gene that encodes p16Ink4a and inhibits the methylation of lysine 27 of the histone H3 locus. However, whether or not JDP2 is able to regulate the chromatin signaling of either p16Ink4a -pRb or Arf-p53, or both, in response to oxidative stress remains elusive...
November 2017: FEBS Open Bio
G S Krasnov, G A Puzanov, A V Kudryavtseva, A A Dmitriev, A D Beniaminov, T T Kondratieva, V N Senchenko
Targeted cancer therapy directed at individual targets is often accompanied by the rapid development of drug resistance. The development of a new generation of antitumor drugs involves the search for many targets simultaneously to block or, conversely, restore their activity. In this regard, simultaneous analysis of gene expression in a complex network of interactions, primarily cell cycle control elements, is relevant for the search of specific molecular markers for the differential diagnosis of adenocarcinoma (ADC) and squamous cell lung cancer (SCC), as well as new targets for therapy...
September 2017: Molekuliarnaia Biologiia
Tatyana Chernova, Fiona A Murphy, Sara Galavotti, Xiao-Ming Sun, Ian R Powley, Stefano Grosso, Anja Schinwald, Joaquin Zacarias-Cabeza, Kate M Dudek, David Dinsdale, John Le Quesne, Jonathan Bennett, Apostolos Nakas, Peter Greaves, Craig A Poland, Ken Donaldson, Martin Bushell, Anne E Willis, Marion MacFarlane
Mesothelioma is a fatal tumor of the pleura and is strongly associated with asbestos exposure. The molecular mechanisms underlying the long latency period of mesothelioma and driving carcinogenesis are unknown. Moreover, late diagnosis means that mesothelioma research is commonly focused on end-stage disease. Although disruption of the CDKN2A (INK4A/ARF) locus has been reported in end-stage disease, information is lacking on the status of this key tumor suppressor gene in pleural lesions preceding mesothelioma...
November 6, 2017: Current Biology: CB
Camelia Nami Saber, Christian Grønhøj, David Hebbelstrup Jensen, Cecilie Nørregaard, Amanda Carlander, Emilie Garnæs, Katalin Kiss, Lena Specht, Christian von Buchwald
INTRODUCTION: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing, but data on the incidence of synchronous, bilateral tonsillar squamous cell carcinomas (BiTSCCs) is sparse. In this study, we report the incidence and tumour characteristics of BiTSCCs in a population-based, consecutive cohort of OPSCCs. METHODS: We identified all patients diagnosed with tonsillar squamous cell carcinoma (TSCC) in eastern Denmark during a 15-year period to detect the incidence of synchronous BiTSCCs...
November 2017: Oral Oncology
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