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MUC16 facilitates cervical cancer progression via JAK2/STAT3 phosphorylation-mediated cyclooxygenase-2 expression

  • Hui ShenEmail author
  • Meng Guo
  • Lu Wang
  • Xinyue Cui
Research Article
  • 39 Downloads

Abstract

Objectives

MUC16 (mucin 16, also known as CA-125, cancer antigen 125, carcinoma antigen 125, or carbohydrate antigen 125) has been predicted as tumor biomarker for therapy. We determined to investigate effects and regulatory mechanism of MUC16 on cervical tumorigenesis.

Methods

Expression levels of MUC16 in cervical cancer cell lines was analyzed via qRT-PCR (quantitative real-time polymerase chain reaction). Knockdown of MUC16 was conducted via shRNA (Short hairpin RNA) transfection. MTT and colony formation assays were used to investigate effect of MUC16 on cell proliferation. Wound healing assay was utilized to detect migration and transwell assay to detect invasion. The underlying mechanism was demonstrated via western blot analysis.

Results

MUC16 was elevated in cervical cancer cell lines. MUC16 knockdown inhibited cell proliferation, invasion and migration. Gain- and loss-of functional assays revealed that over-expression of MUC16 activated Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) via phosphorylation, thus facilitating cyclooxygenase-2 (COX-2) expression, while knockdown of MUC16 demonstrated the reverse effect on JAK2/STAT3 activation and COX-2 expression. Moreover, inhibition of JAK2/STAT3 attenuated the regulation of MUC16 on COX-2.

Conclusions

MUC16 enhanced proliferation and invasion of cervical cancer cells via JAK2/STAT3 phosphorylation-mediated cyclooxygenase-2 expression, suggesting the potential therapeutic target ability of MUC16 to treat cervical cancer.

Keywords

MUC16 JAK2/STAT3 COX-2 Cervical cancer Progression 

Notes

Authors contribution

HS conceived and designed the experiments, MG and LW analyzed and interpreted the results of the experiments, XYC performed the experiments

Funding

This work is partly supported by Science and Technology Development Fund of Nanjing Medical University-Key Project (Grant No. 2017NJMUZD133).

Compliance with ethical standards

Conflict of interest

The authors state that there are no conflicts of interest to disclose.

Ethical approval and consent to participate

The animal use peotocol listed below has been reviewed and approved by the Animal Ethical and Welfaer Committee.

References

  1. Behera R, Kumar V, Lohite K, Karnik S, Kundu GC (2010) Activation of JAK2/STAT3 signaling by osteopontin promotes tumor growth in human breast cancer cells. Carcinogenesis 31:192–200CrossRefGoogle Scholar
  2. Bonneau B, Prudent J, Popgeorgiev N, Gillet G (2013) Non-apoptotic roles of Bcl-2 family: the calcium connection. Biochim Biophys Acta 1833:1755–1765CrossRefGoogle Scholar
  3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424CrossRefGoogle Scholar
  4. Burki TK (2018) Outcomes after minimally invasive surgery in cervical cancer. Lancet Oncol 19:e674CrossRefGoogle Scholar
  5. Clarke CH, Yip C, Badgwell D, Fung ET, Coombes KR, Zhang Z, Lu KH, Bast RC Jr (2011) Proteomic biomarkers apolipoprotein A1, truncated transthyretin and connective tissue activating protein III enhance the sensitivity of CA125 for detecting early stage epithelial ovarian cancer. Gynecol Oncol 122:548–553CrossRefGoogle Scholar
  6. Fan Z, Cui H, Xu X, Lin Z, Zhang X, Kang L, Han B, Meng J, Yan Z, Yan X et al (2015) MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3. Oncotarget 6:25266–25280PubMedPubMedCentralGoogle Scholar
  7. Feng L, Wang Z (2006) Chemopreventive effect of celecoxib in oral precancers and cancers. Laryngoscope 116:1842–1845CrossRefGoogle Scholar
  8. Fujimoto J, Toyoki H, Sato E, Sakaguchi H, Jahan I, Alam SM, Tamaya T (2006) Expression of cyclooxygenase-2 related to angiogenesis in uterine cervical cancers. J Biomed Sci 13:825–832CrossRefGoogle Scholar
  9. Gao J, Tian J, Lv Y, Shi F, Kong F, Shi H, Zhao L (2009) Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. Cancer Sci 100:389–395CrossRefGoogle Scholar
  10. Hovland S, Muller S, Skomedal H, Mints M, Bergstrom J, Wallin KL, Karlsen F, Johansson B, Andersson S (2010) E6/E7 mRNA expression analysis: a test for the objective assessment of cervical adenocarcinoma in clinical prognostic procedure. Int J Oncol 36:1533–1539PubMedGoogle Scholar
  11. Kanaoka S, Takai T, Yoshida K (2007) Cyclooxygenase-2 and tumor biology. Adv Clin Chem 43:59–78CrossRefGoogle Scholar
  12. Khalil J, Bellefqih S, Sahli N, Afif M, Elkacemi H, Elmajjaoui S, Kebdani T, Benjaafar N (2015) Impact of cervical cancer on quality of life: beyond the short term (results from a single institution): quality of life in long-term cervical cancer survivors: results from a single institution. Gynecol Oncol Res Pract 2:7CrossRefGoogle Scholar
  13. Kundu J, Choi BY, Jeong CH, Kundu JK, Chun KS (2014) Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Srcmediated phosphorylation of EGF receptor tyrosine kinase. Oncol Rep 32:821–828CrossRefGoogle Scholar
  14. Lakshmanan I, Ponnusamy MP, Das S, Chakraborty S, Haridas D, Mukhopadhyay P, Lele SM, Batra SK (2012) MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells. Oncogene 31:805–817CrossRefGoogle Scholar
  15. Li H, Lu Y, Pang Y, Li M, Cheng X, Chen J (2017) Propofol enhances the cisplatin-induced apoptosis on cervical cancer cells via EGFR/JAK2/STAT3 pathway. Biomed Pharmacother 86:324–333CrossRefGoogle Scholar
  16. Porika M, Vemunoori AK, Tippani R, Mohammad A, Bollam SR, Abbagani S (2010) Squamous cell carcinoma antigen and cancer antigen 125 in southern Indian cervical cancer patients. Asian Pac J Cancer Prev 11:1745–1747PubMedGoogle Scholar
  17. Qureshi R, Arora H, Rizvi MA (2015) EMT in cervical cancer: its role in tumour progression and response to therapy. Cancer Lett 356:321–331CrossRefGoogle Scholar
  18. Shimizu A, Hirono S, Tani M, Kawai M, Okada K, Miyazawa M, Kitahata Y, Nakamura Y, Noda T, Yokoyama S et al (2012) Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma. Cancer Sci 103:739–746CrossRefGoogle Scholar
  19. Shukla SK, Gunda V, Abrego J, Haridas D, Mishra A, Souchek J, Chaika NV, Yu F, Sasson AR, Lazenby AJ et al (2015) MUC16-mediated activation of mTOR and c-Myc reprograms pancreatic cancer metabolism. Oncotarget 6:19118–19131PubMedPubMedCentralGoogle Scholar
  20. Sturgeon CM, Duffy MJ, Hofmann BR, Lamerz R, Fritsche HA, Gaarenstroom K, Bonfrer J, Ecke TH, Grossman HB, Hayes P et al (2010) National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin Chem 56:e1–48CrossRefGoogle Scholar
  21. Takaoka K, Kishimoto H, Segawa E, Hashitani S, Zushi Y, Noguchi K, Sakurai K, Urade M (2006) Elevated cell migration, invasion and tumorigenicity in human KB carcinoma cells transfected with COX-2 cDNA. Int J Oncol 29:1095–1101PubMedGoogle Scholar
  22. Teng Y, Ross JL, Cowell JK (2014) The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT 3:e28086PubMedPubMedCentralGoogle Scholar
  23. Tzafetas M, Mitra A, Kalliala I, Lever S, Fotopoulou C, Farthing A, Smith JR, Martin-Hirsch P, Paraskevaidis E, Kyrgiou M (2018) Fertility-sparing surgery for presumed early-stage invasive cervical cancer: a survey of practice in the United Kingdom. Anticancer Res 38:3641–3646CrossRefGoogle Scholar
  24. Wang Q, Shi G, Teng Y, Li X, Xie J, Shen Q, Zhang C, Ni S, Tang Z (2017) Successful reduction of inflammatory responses and arachidonic acid-cyclooxygenase 2 pathway in human pulmonary artery endothelial cells by silencing adipocyte fatty acid-binding protein. J Inflamm (Lond) 14:8CrossRefGoogle Scholar
  25. Xu W, Chen GS, Shao Y, Li XL, Xu HC, Zhang H, Zhu GQ, Zhou YC, He XP, Sun WH (2013) Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells. Cancer Lett 332:11–18CrossRefGoogle Scholar
  26. Zhu L, Tu H, Liang Y, Tang D (2018) MiR-218 produces anti-tumor effects on cervical cancer cells in vitro. World J Surg Oncol 16:204CrossRefGoogle Scholar

Copyright information

© The Genetics Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Gynaecology and ObstetricsThe Affiliated Sir Run Run Hospital of Nanjing Medical UniversityNanjingChina

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