Skip to main content
SpringerLink
Log in

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

  • Research Article
  • Published:
Genes & Genomics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

References

  • 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 31:192–200

    Article  CAS  Google Scholar 

  • Bonneau B, Prudent J, Popgeorgiev N, Gillet G (2013) Non-apoptotic roles of Bcl-2 family: the calcium connection. Biochim Biophys Acta 1833:1755–1765

    Article  CAS  Google Scholar 

  • 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 68:394–424

    Article  Google Scholar 

  • Burki TK (2018) Outcomes after minimally invasive surgery in cervical cancer. Lancet Oncol 19:e674

    Article  Google Scholar 

  • 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 122:548–553

    Article  CAS  Google Scholar 

  • 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 6:25266–25280

    PubMed  PubMed Central  Google Scholar 

  • Feng L, Wang Z (2006) Chemopreventive effect of celecoxib in oral precancers and cancers. Laryngoscope 116:1842–1845

    Article  CAS  Google Scholar 

  • 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 13:825–832

    Article  CAS  Google Scholar 

  • 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 100:389–395

    Article  CAS  Google Scholar 

  • 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 36:1533–1539

    PubMed  Google Scholar 

  • Kanaoka S, Takai T, Yoshida K (2007) Cyclooxygenase-2 and tumor biology. Adv Clin Chem 43:59–78

    Article  CAS  Google Scholar 

  • 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 2:7

    Article  CAS  Google Scholar 

  • 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 32:821–828

    Article  Google Scholar 

  • 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 31:805–817

    Article  CAS  Google Scholar 

  • 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 86:324–333

    Article  CAS  Google Scholar 

  • 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 11:1745–1747

    PubMed  Google Scholar 

  • Qureshi R, Arora H, Rizvi MA (2015) EMT in cervical cancer: its role in tumour progression and response to therapy. Cancer Lett 356:321–331

    Article  CAS  Google Scholar 

  • 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 103:739–746

    Article  CAS  Google Scholar 

  • 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 6:19118–19131

    PubMed  PubMed Central  Google Scholar 

  • 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:e1–48

    Article  CAS  Google Scholar 

  • 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 29:1095–1101

    CAS  PubMed  Google Scholar 

  • Teng Y, Ross JL, Cowell JK (2014) The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT 3:e28086

    PubMed  PubMed Central  Google Scholar 

  • 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 38:3641–3646

    Article  Google Scholar 

  • 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) 14:8

    Article  Google Scholar 

  • 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 332:11–18

    Article  CAS  Google Scholar 

  • 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 16:204

    Article  Google Scholar 

Download references

Funding

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

Author information

Authors and Affiliations

  1. Department of Gynaecology and Obstetrics, The Affiliated Sir Run Run Hospital of Nanjing Medical University, No. 109 Longmian Avenue, Jiangning District, Nanjing, 211166, China

    Hui Shen, Meng Guo, Lu Wang & Xinyue Cui

Authors
  1. Hui Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinyue Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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

Corresponding author

Correspondence to Hui Shen.

Ethics declarations

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, H., Guo, M., Wang, L. et al. MUC16 facilitates cervical cancer progression via JAK2/STAT3 phosphorylation-mediated cyclooxygenase-2 expression. Genes Genom 42, 127–133 (2020). https://doi.org/10.1007/s13258-019-00885-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13258-019-00885-9

Keywords

Search

Navigation