Bioinformatics-driven Identification of lncRNA LINC02381 in Mediating Cisplatin Resistance via IL-12 Induced Wnt/TCF7 Signaling in Ovarian Cancer
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Abstract
Cisplatin resistance presents a considerable hurdle in the treatment of ovarian cancer, significantly impacting patient outcomes and limiting the effectiveness of chemotherapy. This study employs advanced bioinformatics techniques-including RNA sequencing (RNA-seq), DNA sequencing (DNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq)-to elucidate the molecular mechanisms underlying this resistance, with a particular focus on the long non-coding RNA (lncRNA) LINC02381.
Our findings reveal that LINC02381 is significantly upregulated in ovarian cancer cells exhibiting resistance to cisplatin, suggesting its pivotal role in mediating this phenomenon. We further demonstrate that cytokines, particularly interleukin-12 (IL-12), secreted by immune cells within the tumor microenvironment, activate the Wnt signaling pathway. This activation leads to the binding of the transcription factor TCF7 to the promoter region of LINC02381, resulting in enhanced expression of this lncRNA.
Notably, this interaction establishes a positive feedback loop in which LINC02381 not only promotes its own expression but also amplifies Wnt signaling activity. This cascade ultimately drives the upregulation of ATP-binding cassette (ABC) transporters, which are crucial for the efflux of cisplatin from cancer cells. Thus, the drug's intracellular concentration is reduced, and cell survival under chemotherapy pressure is facilitated. These insights uncover a novel mechanism of cisplatin resistance driven by the IL-12/Wnt/TCF7/LINC02381 axis, highlighting the complex interplay between immune signaling and drug resistance in ovarian cancer.
Our findings suggest that targeting this regulatory pathway may offer promising therapeutic strategies to overcome chemotherapy resistance, paving the way for improved treatment outcomes in patients with ovarian cancer. Future research should focus on validating these mechanisms and exploring potential interventions that disrupt this feedback loop.
2. Zoń A, Bednarek I. Cisplatin in ovarian cancer treatment—known limitations in therapy force new solutions. Int J Mol Sci. 2023;24(8):7585.
3. Zhu S, Pabla N, Tang C, He L, Dong Z. DNA damage response in cisplatin-induced nephrotoxicity. Arch Toxicol. 2015;89:2197-205.
4. Hombach S, Kretz M. Non-coding RNAs: classification, biology and functioning. Non-coding RNAs in colorectal cancer. Adv Exp Med Biol. 2016:3-17.
5. Barth DA, Juracek J, Slaby O, Pichler M, Calin GA. lncRNA and mechanisms of drug resistance in cancers of the genitourinary system. Cancers. 2020;12(8):2148.
6. Miraghel SA, Ebrahimi N, Khani L, Mansouri A, Jafarzadeh A, Ahmadi A, et al. Crosstalk between non-coding RNAs expression profile, drug resistance and immune response in breast cancer. Pharmacoll Res. 2022;176:106041.
7. Zhang J, Wu Y, Mu J, Xin D, Wang L, Fan Y, et al. Glycosyltransferase-related long non-coding RNA signature predicts the prognosis of colon adenocarcinoma. Front Oncol. 2022;12:954226.
8. Li X, Xiang Y, Li F, Yin C, Li B, Ke X. WNT/β-catenin signaling pathway regulating T cell-inflammation in the tumor microenvironment. Front Immunol. 2019;10:2293.
9. Hrckulak D, Kolar M, Strnad H, Korinek V. TCF/LEF transcription factors: an update from the internet resources. Cancers. 2016;8(7):70.
10. Wang J, Zhao Q. Linc02381 exacerbates rheumatoid arthritis through adsorbing miR-590-5p and activating the mitogen-activated protein kinase signaling pathway in rheumatoid arthritis-fibroblast-like synoviocytes. Cell Transplant. 2020;29:0963689720938023.
11. Hass R, von der Ohe J, Ungefroren H. Impact of the tumor microenvironment on tumor heterogeneity and consequences for cancer cell plasticity and stemness. Cancers. 2020;12(12):3716.
12. Goldsberry WN, Londoño A, Randall TD, Norian LA, Arend RC. A review of the role of Wnt in cancer immunomodulation. Cancers. 2019;11(6):771.
13. Kim C, Jin J, Weyand CM, Goronzy JJ. The transcription factor TCF1 in T cell differentiation and aging. Int J Mol Sci. 2020;21(18):6497.
14 Dréan A, Rosenberg S, Lejeune F-X, Goli L, Nadaradjane AA, Guehennec J, et al. ATP binding cassette (ABC) transporters: expression and clinical value in glioblastoma. J Neurooncol. 2018;138:479-86.
15. Vesel M, Rapp J, Feller D, Kiss E, Jaromi L, Meggyes M, et al. ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling. Resp Res. 2017;18:1-11.
16. Mirlekar B, Pylayeva-Gupta Y. IL-12 family cytokines in cancer and immunotherapy. Cancers. 2021;13(2):167.
17. Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, et al. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol. 2021;14(1):156.
18. Shan C, Liang Y, Wang K, Li P. Noncoding RNAs in cancer ferroptosis: from biology to clinical opportunity. Biomed Pharmacother. 2023;165:115053.
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| Keywords | ||
| Cisplatin resistance IL12 LINC02381 TCF7 Ovarian cancer Wnt signaling | ||
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