TY - JOUR
T1 - MUC16 regulates TSPYL5 for lung cancer cell growth and chemoresistance by suppressing p53
AU - Lakshmanan, Imayavaramban
AU - Salfity, Shereen
AU - Seshacharyulu, Parthasarathy
AU - Rachagani, Satyanarayana
AU - Thomas, Abigail
AU - Das, Srustidhar
AU - Majhi, Prabin D.
AU - Nimmakayala, Rama Krishna
AU - Vengoji, Raghupathy
AU - Lele, Subodh M.
AU - Ponnusamy, Moorthy P.
AU - Batra, Surinder K.
AU - Ganti, Apar Kishor
N1 - Funding Information:
The authors acknowledge the valuable technical support from Kavita Mallya, Microarray Core Facility for gene expression analysis, Cell Sorting Facilities for cell-cycle/apoptosis analysis, and the Confocal Facility for imaging assistance. The work is partly supported by grants from the US Department of Veterans' Affairs, UNMC Department of Internal Medicine Summer Undergraduate Research Program, Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727), and NIH (UO1 CA111294, P50 CA127297, U54 CA163120, RO1 CA183459, RO1 CA195586, K22 CA175260, and P20 GM103480). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/7/15
Y1 - 2017/7/15
N2 - 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.
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 (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.
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U2 - 10.1158/1078-0432.CCR-16-2530
DO - 10.1158/1078-0432.CCR-16-2530
M3 - Article
C2 - 28196872
AN - SCOPUS:85024099643
SN - 1078-0432
VL - 23
SP - 3906
EP - 3917
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -