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MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53.

ABSTRACT: Purpose: MUC16, a tumor biomarker and cell surface-associated mucin, is overexpressed in various cancers; however, its role in lung cancer pathogenesis is unknown. Here, we have explored the mechanistic role of MUC16 in lung cancer.Experimental Design: To identify the functional role of MUC16, stable knockdown was carried in lung cancer cells with two different shRNAs. Clinical significance of MUC16 was evaluated in lung cancer patient tissues using IHC. We have generated genetically engineered mouse model (KrasG12D; AdCre) to evaluate the preclinical significance of MUC16.Results: MUC16 was overexpressed (P = 0.03) in lung cancer as compared with normal tissues. MUC16 knockdown (KD) in lung cancer cell lines decreased the in vitro growth rate (P < 0.05), migration (P < 0.001), and in vivo tumor growth (P = 0.007), whereas overexpression of MUC16-carboxyl terminal (MUC16-Cter) resulted in increased growth rate (P < 0.001). Transcriptome analysis of MUC16 KD showed a downregulation (P = 0.005) of TSPYL5 gene, which encodes for a testis-specific Y-like protein. Rescue studies via overexpression of MUC16-Cter in MUC16 KD cells showed activation of signaling proteins, such as JAK2 (Y1007/1008), STAT3 (Y705), and glucocorticoid receptor (GR), which constitutes an important axis for the regulation of TSPYL5 for oncogenic process. Further, inhibition of STAT3 (Y705) led to decreased GR and TSPYL5, suggesting that MUC16 regulates TSPYL5 through the JAK2/STAT3/GR axis. Also, MUC16 overexpression induced cisplatin and gemcitabine resistance by downregulation of p53.Conclusions: Our findings indicate a significant role of MUC16 in tumorigenesis and metastasis of lung cancer cells possibly via regulation of TSPYL5 through the JAK2/STAT3/GR axis. Clin Cancer Res; 23(14); 3906-17. ©2017 AACR.

SUBMITTER: Lakshmanan I

PROVIDER: S-EPMC5511558 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53.

Lakshmanan Imayavaramban I Salfity Shereen S Seshacharyulu Parthasarathy P Rachagani Satyanarayana S Thomas Abigail A Das Srustidhar S Majhi Prabin D PD Nimmakayala Rama Krishna RK Vengoji Raghupathy R Lele Subodh M SM Ponnusamy Moorthy P MP Batra Surinder K SK Ganti Apar Kishor AK

Clinical cancer research : an official journal of the American Association for Cancer Research 20170214 14

<b>Purpose:</b> MUC16, a tumor biomarker and cell surface-associated mucin, is overexpressed in various cancers; however, its role in lung cancer pathogenesis is unknown. Here, we have explored the mechanistic role of MUC16 in lung cancer.<b>Experimental Design:</b> To identify the functional role of MUC16, stable knockdown was carried in lung cancer cells with two different shRNAs. Clinical significance of MUC16 was evaluated in lung cancer patient tissues using IHC. We have generated genetical ...[more]

PMID: 28196872

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Project description:The highly refractory nature of non-small cell lung cancer (NSCLC) to chemotherapeutic drugs is an important factor resulting in its poor prognosis. Recent studies have revealed that tumour necrosis factor alpha-induced protein 8 (TNFAIP8) is involved in various biological and pathological processes of cells, but their underlying mechanisms in processes ranging from cancer development to drug resistance have not been fully elucidated.TNFAIP8 expression in clinical NSCLC samples was examined through immunohistochemistry (IHC). After adjusting for patients' characteristics with propensity score matching, Kaplan-Meier analysis and Cox regression analysis were performed for comparison of patients' survival according to the TNFAIP8 level. Lentiviral transfection with TNFAIP8-specific shRNAs was used to establish stable TNFAIP8 knockdown (TNFAIP8 KD) NCI-H460, A549 and cis-diamminedichloroplatinum II resistant A549 (A549/cDDP) cell lines. Cell proliferation and viability were assessed by CCK-8 assay. Cell cycle was examined by flow cytometry. Multiple pathways regulated by TNFAIP8 KD were revealed by microarray analysis.We found that high TNFAIP8 expression was associated with advanced pT stage, advanced pTNM stage, lymph node metastasis and unfavourable survival in NSCLC patients. TNFAIP8 shRNAs reduced in vitro cancer cell proliferation and in vivo tumor growth. Additionally, TNFAIP8 KD increased the sensitivity of NSCLC cells to cisplatin in vitro and in vivo. Conversely, up-regulation of TNFAIP8 promoted the?proliferation and?drug resistance to cisplatin?of NSCLC cells. TNFAIP8 influences cancer progression pathways involving the MDM2/p53 pathway. Indeed, we observed that TNFAIP8 KD mediated the MDM2 downregulation and the p53 ubiquitination, thereby decreasing the degradation of p53 protein. shRNA p53 reversed TNFAIP8 shRNA-mediated regulation of cell proliferation, cell cycle, cisplatin sensitivity, and expression levels of RAD51, a DNA repair gene.Our work uncovers a hitherto unappreciated role of TNFAIP8 in NSCLC proliferation and cisplatin chemoresistance that is mediated through the MDM2/p53 pathway. These findings might offer potential therapeutic targets for reversing cisplatin resistance in NSCLC patients with high TNFAIP8 expression.

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MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53.

Publications

MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53.

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