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NPHS2-6 drives cervical squamous cell carcinoma (CSCC) progression via hsa-miR-1323/SMC1B axis to activate PI3K-Akt pathway

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Abstract

Purpose

A substantial amount of evidence demonstrates suggests that long non-coding RNAs (lncRNAs) play a key role in the progression of various malignancies, cervical squamous cell carcinoma (CSCC) included. In our study, we deeply investigated the role and molecular mechanism of lncRNA NPHS2-6 in CSCC.

Methods

The expression level of gene and protein expression were measured by qRT-PCR and western blot. To test the cell proliferation and cell metastasis ability, we carried out the CCK-8 experiment, clone formation assay, transwell assay and wound healing, respectively. The interactivity among NPHS2-6, miR-1323 and SMC1B were co demonstrated using the bioinformatics tool, dual-luciferase reporter system, and RNA pulldown assay. The subcutaneous tumor model of nude mice was established to verify the results of previous studies at the in vivo. NPHS2-6 was upregulated in CSCC tissues and cells.

Results

NPHS2-6 deficiency significantly inhibited CSCC cell growth and EMT in vitro. In addition, NPHS2-6 deficiency also inhibited the growth of CSCC xenograft tumors in mice in vivo. Importantly, NPHS2-6 was a competing endogenous RNA (ceRNA) to increases SMC1B levels by binding to miR-1323, leading to activate the PI3K/Akt pathway, thereby exacerbating tumorigenesis of CSCC.

Conclusions

In conclusion, NPHS2-6/miR-1323/SMC1B/PI3K/Akt signaling accelerates the progression of CSCC, providing a new direction for the treatment strategy of CSCC.

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References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.

    Article  CAS  PubMed  Google Scholar 

  2. Hildesheim A, Gonzalez P, Kreimer AR, Wacholder S, Schussler J, Rodriguez AC, et al. Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment. Am J Obstet Gynecol. 2016;215(2):212.e1-212.e15.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Article  PubMed  Google Scholar 

  4. Groves IJ, Coleman N. Pathogenesis of human papillomavirus-associated mucosal disease. J Pathol. 2015;235(4):527–38.

    Article  CAS  PubMed  Google Scholar 

  5. Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013;382(9895):889–99.

    Article  PubMed  Google Scholar 

  6. Qin W, Dong P, Ma C, Mitchelson K, Deng T, Zhang L, et al. MicroRNA-133b is a key promoter of cervical carcinoma development through the activation of the ERK and AKT1 pathways. Oncogene. 2012;31(36):4067–75.

    Article  CAS  PubMed  Google Scholar 

  7. Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18(2):128–34.

    Article  CAS  PubMed  Google Scholar 

  8. Wrighton KH. Cell migration: EMT promotes contact inhibition of locomotion. Nat Rev Mol Cell Biol. 2015;16(9):518.

    Article  CAS  PubMed  Google Scholar 

  9. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119(6):1429–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Márton É, Lukács J, Penyige A, Janka E, Hegedüs L, Soltész B, et al. Circulating epithelial-mesenchymal transition-associated miRNAs are promising biomarkers in ovarian cancer. J Biotechnol. 2019;297:58–65.

    Article  PubMed  Google Scholar 

  11. Fang Y, Fullwood MJ. Roles, functions, and mechanisms of long non-coding RNAs in cancer. Genomics Proteom Bioinform. 2016;14(1):42–54.

    Article  CAS  Google Scholar 

  12. Wu Q, Xiang S, Ma J, Hui P, Wang T, Meng W, et al. Long non-coding RNA CASC15 regulates gastric cancer cell proliferation, migration and epithelial mesenchymal transition by targeting CDKN1A and ZEB1. Mol Oncol. 2018;12(6):799–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huang Y, Xiang B, Liu Y, Wang Y, Kan H. LncRNA CDKN2B-AS1 promotes tumor growth and metastasis of human hepatocellular carcinoma by targeting let-7c-5p/NAP1L1 axis. Cancer Lett. 2018;437:56–66.

    Article  CAS  PubMed  Google Scholar 

  14. Yang G, Lu X, Yuan L. LncRNA: a link between RNA and cancer. Biochim Biophys Acta. 2014;1839(11):1097–109.

    Article  CAS  PubMed  Google Scholar 

  15. Tsai MC, Spitale RC, Chang HY. Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 2011;71(1):3–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hou A, Zhang Y, Fan Y, Zheng Y, Zhou X, Liu H. LncRNA MAGI2-AS3 affects cell invasion and migration of cervical squamous cell carcinoma (CSCC) via sponging miRNA-233/EPB41L3 axis. Cancer Manag Res. 2020;12:4209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ta W, Zhang Y, Zhang S, Sun P. LncRNA ANCR downregulates hypoxia-inducible factor 1α and inhibits the growth of HPV-negative cervical squamous cell carcinoma under hypoxic conditions. Mol Med Rep. 2020;21(1):413–9.

    CAS  PubMed  Google Scholar 

  18. Liu H, Zhu C, Xu Z, Wang J, Qian L, Zhou Q, et al. lncRNA PART1 and MIR17HG as ΔNp63α direct targets regulate tumor progression of cervical squamous cell carcinoma. Cancer Sci. 2020;111(11):4129–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kartha RV, Subramanian S. Competing endogenous RNAs (ceRNAs): new entrants to the intricacies of gene regulation. Front Genet. 2014;5:8.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chen Y, Wu Q, Lin J, Wei J. DARS-AS1 accelerates the proliferation of cervical cancer cells via miR-628-5p/JAG1 axis to activate Notch pathway. Cancer Cell Int. 2020;20(1):535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xu P, Li X, Liang Y, Bao Z, Zhang F, Gu L, et al. PmiRtarbase: a positive miRNA-target regulations database. Comput Biol Chem. 2022;98: 107690.

    Article  CAS  PubMed  Google Scholar 

  22. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–79.

    Article  CAS  PubMed  Google Scholar 

  23. Zare M, Bastami M, Solali S, Alivand MR. Aberrant miRNA promoter methylation and EMT-involving miRNAs in breast cancer metastasis: diagnosis and therapeutic implications. J Cell Physiol. 2018;233(5):3729–44.

    Article  CAS  PubMed  Google Scholar 

  24. Jurisic V, Obradovic J, Nikolic N, Javorac J, Perin B, Milasin J. Analyses of P16(INK4a) gene promoter methylation relative to molecular, demographic and clinical parameters characteristics in non-small cell lung cancer patients: a pilot study. Mol Biol Rep. 2023;50(2):971–9.

    Article  CAS  PubMed  Google Scholar 

  25. Shi WJ, Liu H, Ge YF, Wu D, Tan YJ, Shen YC, et al. LINC00673 exerts oncogenic function in cervical cancer by negatively regulating miR-126-5p expression and activates PTEN/PI3K/AKT signaling pathway. Cytokine. 2020;136: 155286.

    Article  CAS  PubMed  Google Scholar 

  26. Li R, Huang D, Ju M, Chen HY, Luan C, Zhang JA, et al. The long non-coding RNA PVT1 promotes tumorigenesis of cutaneous squamous cell carcinoma via interaction with 4EBP1. Cell Death Discov. 2023;9(1):101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jurisic V, Srdic-Rajic T, Konjevic G, Bogdanovic G, Colic M. TNF-α induced apoptosis is accompanied with rapid CD30 and slower CD45 shedding from K-562 cells. J Membr Biol. 2011;239(3):115–22.

    Article  CAS  PubMed  Google Scholar 

  28. Liu Y, Shi M, He X, Cao Y, Liu P, Li F, et al. LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma. J Hematol Oncol. 2022;15(1):52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, et al. The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget. 2015;6(26):22513–25.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang L, Cho KB, Li Y, Tao G, Xie Z, Guo B. Long noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal cancer. Int J Mol Sci. 2019;20(22):5758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: a new paradigm. Cancer Res. 2017;77(15):3965–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cheng H, Tian J, Wang C, Ren L, Wang N. LncRNA BLACAT1 is upregulated in cervical squamous cell carcinoma (CSCC) and predicts poor survival. Reprod Sci. 2020;27(2):585–91.

    Article  PubMed  Google Scholar 

  33. Dong J, Su M, Chang W, Zhang K, Wu S, Xu T. Long non-coding RNAs on the stage of cervical cancer. Oncol Rep. 2017;38(4):1923–31.

    Article  CAS  PubMed  Google Scholar 

  34. No authors listed. Expression of concern: LncRNA SRA1 is downregulated in HPV-negative cervical squamous cell carcinoma (CSCC) and regulates cancer cell behaviors. Biosci Rep. 2020;40(7):BSR-20191226_EOC.

  35. Zhu J, Zhang X, Gao W, Hu H, Wang X, Hao D. lncRNA/circRNA-miRNA-mRNA ceRNA network in lumbar intervertebral disc degeneration. Mol Med Rep. 2019;20(4):3160–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhou RS, Zhang EX, Sun QF, Ye ZJ, Liu JW, Zhou DH, et al. Integrated analysis of lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of tongue. BMC Cancer. 2019;19(1):779.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work is supported by the project of Science and Technology Department of Xinjiang Uygur Autonomous Region (No. 2020E02125 and No. 2020D01C204).

Author information

Author notes

  1. Fen Li and Yan Wang have contributed equally to this work.

Authors and Affiliations

  1. The Second Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, 789 Suzhou East Street, Urumqi, 830011, Xinjiang Province, China

    Fen Li, Mengke Wen, Gulibiya Aizezi, Jinrui Yuan, Tongjunnan Zhou & Guqun Shen

  2. Key Laboratory of Oncology of Xinjiang Uyghur Autonomous Region, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, 830011, China

    Yan Wang

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  1. Fen Li
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Contributions

FL and YW conceived and designed the study, and drafted the manuscript. MW, GA and JY collected, analyzed and interpreted the experimental data. TZ and GS revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Guqun Shen.

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The study was approved by Ethical Committee of Affiliated Tumor Hospital of Xinjiang Medical University and conducted in accordance with the ethical standards.

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Li, F., Wang, Y., Wen, M. et al. NPHS2-6 drives cervical squamous cell carcinoma (CSCC) progression via hsa-miR-1323/SMC1B axis to activate PI3K-Akt pathway. Clin Transl Oncol 26, 245–259 (2024). https://doi.org/10.1007/s12094-023-03248-9

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  • DOI: https://doi.org/10.1007/s12094-023-03248-9

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