title: 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 thein vitrogrowth rate (P< 0.05), migration (P< 0.001), andin vivotumor 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Imayavaramban
authors.initials: I
authors.lastname: Lakshmanan
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Shereen
authors.initials: S
authors.lastname: Salfity
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Seshacharyulu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Abigail
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Srustidhar
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Prabin D
authors.initials: PD
authors.lastname: Majhi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Rama Krishna
authors.initials: RK
authors.lastname: Nimmakayala
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Raghupathy
authors.initials: R
authors.lastname: Vengoji
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Subodh M
authors.initials: SM
authors.lastname: Lele
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.|Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett Cancer Center University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Moorthy P
authors.initials: MP
authors.lastname: Ponnusamy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. aganti@unmc.edu sbatra@unmc.edu.|Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett Cancer Center University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. aganti@unmc.edu sbatra@unmc.edu.|Department of Internal Medicine, VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Apar Kishor
authors.initials: AK
authors.lastname: Ganti
mesh_terms: D000072283:A549 Cells; D000818:Animals; D018394:CA-125 Antigen / Q000235:genetics*; D002465:Cell Movement; D049109:Cell Proliferation / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C495901:TP53 protein, human; C527859:TSPYL5 protein, human; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D053614:Janus Kinase 2; D002945:Cisplatin; D000093542:Gemcitabine