PMID- 28196872
OWN - NLM
STAT- MEDLINE
DCOM- 20180409
LR  - 20221207
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 23
IP  - 14
DP  - 2017 Jul 15
TI  - MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by 
      Suppressing p53.
PG  - 3906-3917
LID - 10.1158/1078-0432.CCR-16-2530 [doi]
AB  - 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 (Kras(G12D); 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. (c)2017 AACR.
CI  - (c)2017 American Association for Cancer Research.
FAU - Lakshmanan, Imayavaramban
AU  - Lakshmanan I
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
FAU - Salfity, Shereen
AU  - Salfity S
AD  - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, 
      Nebraska.
FAU - Seshacharyulu, Parthasarathy
AU  - Seshacharyulu P
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
FAU - Rachagani, Satyanarayana
AU  - Rachagani S
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
FAU - Thomas, Abigail
AU  - Thomas A
AD  - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, 
      Nebraska.
FAU - Das, Srustidhar
AU  - Das S
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
FAU - Majhi, Prabin D
AU  - Majhi PD
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
FAU - Nimmakayala, Rama Krishna
AU  - Nimmakayala RK
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
FAU - Vengoji, Raghupathy
AU  - Vengoji R
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
FAU - Lele, Subodh M
AU  - Lele SM
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, Nebraska.
FAU - Ponnusamy, Moorthy P
AU  - Ponnusamy MP
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska.
AD  - Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett 
      Cancer Center University of Nebraska Medical Center, Omaha, Nebraska.
FAU - Batra, Surinder K
AU  - Batra SK
AD  - Department of Biochemistry and Molecular Biology, University of Nebraska Medical 
      Center, Omaha, Nebraska. aganti@unmc.edu sbatra@unmc.edu.
AD  - Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett 
      Cancer Center University of Nebraska Medical Center, Omaha, Nebraska.
FAU - Ganti, Apar Kishor
AU  - Ganti AK
AD  - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, 
      Nebraska. aganti@unmc.edu sbatra@unmc.edu.
AD  - Department of Internal Medicine, VA Nebraska-Western Iowa Health Care System and 
      University of Nebraska Medical Center, Omaha, Nebraska.
LA  - eng
GR  - U54 CA163120/CA/NCI NIH HHS/United States
GR  - U01 CA111294/CA/NCI NIH HHS/United States
GR  - R01 CA195586/CA/NCI NIH HHS/United States
GR  - P50 CA127297/CA/NCI NIH HHS/United States
GR  - P30 CA036727/CA/NCI NIH HHS/United States
GR  - K22 CA175260/CA/NCI NIH HHS/United States
GR  - R01 CA183459/CA/NCI NIH HHS/United States
GR  - P20 GM103480/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20170214
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (CA-125 Antigen)
RN  - 0 (MUC16 protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (TP53 protein, human)
RN  - 0 (TSPYL5 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0W860991D6 (Deoxycytidine)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - Q20Q21Q62J (Cisplatin)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - A549 Cells
MH  - Animals
MH  - CA-125 Antigen/*genetics
MH  - Cell Movement
MH  - Cell Proliferation/genetics
MH  - Cisplatin/administration & dosage
MH  - Deoxycytidine/administration & dosage/analogs & derivatives
MH  - Disease Models, Animal
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Janus Kinase 2/genetics
MH  - Lung Neoplasms/*drug therapy/genetics/pathology
MH  - Membrane Proteins/*genetics
MH  - Mice
MH  - Nuclear Proteins/*genetics
MH  - STAT3 Transcription Factor/genetics
MH  - Tumor Suppressor Protein p53/*genetics
MH  - Gemcitabine
PMC - PMC5511558
MID - NIHMS853467
COIS- Disclosure of Potential Conflicts of Interest The authors declare that they have 
      no conflicts of interest.
EDAT- 2017/02/16 06:00
MHDA- 2018/04/10 06:00
PMCR- 2018/07/15
CRDT- 2017/02/16 06:00
PHST- 2016/10/11 00:00 [received]
PHST- 2016/12/12 00:00 [revised]
PHST- 2017/01/28 00:00 [accepted]
PHST- 2017/02/16 06:00 [pubmed]
PHST- 2018/04/10 06:00 [medline]
PHST- 2017/02/16 06:00 [entrez]
PHST- 2018/07/15 00:00 [pmc-release]
AID - 1078-0432.CCR-16-2530 [pii]
AID - 10.1158/1078-0432.CCR-16-2530 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2017 Jul 15;23(14):3906-3917. doi: 
      10.1158/1078-0432.CCR-16-2530. Epub 2017 Feb 14.