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Transcription Factor STAT3-Activated LDHB Promotes Tumor Properties of Endometrial Cancer Cells by Inducing MDH2 Expression

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Abstract

The pathogenesis of endometrial cancer (EC) involves the regulation of lactate dehydrogenases. However, the role and mechanism of lactate dehydrogenase-B (LDHB) in EC progression have not been studied. The mRNA levels of LDHB and malate dehydrogenase 2 (MDH2) were detected by quantitative real-time polymerase chain reaction. Protein expression was checked by western blotting and immunohistochemistry assays. Cell proliferation, apoptosis, and invasion were analyzed by 5-Ethynyl-2’-deoxyuridine, transwell, and flow cytometry assay, respectively. Glycolysis was investigated using Glucose Assay Kit, CheKine™ Micro Lactate Assay Kit, and ADP/ATP ratio assay kit. An in vivo tumor formation assay was conducted to disclose the effect of LDHB on tumor growth in vivo. The associations among signal transducer and activator of transcription 3 (STAT3), LDHB, and MDH2 were predicted through JASPAR or GeneMANIA online database and identified by chromatin immunoprecipitation assay, dual-luciferase reporter assay, and co-immunoprecipitation assay. LDHB expression was increased in EC tissues and cells in comparison with normal endometrial tissues and human endometrial stromal cells. LDHB had the potential as a biomarker to predict the prognosis of EC patients. In addition, LDHB knockdown inhibited the proliferation, invasion, and glycolysis and promoted apoptosis of RL95-2 and Ishikawa cells. LDHB knockdown inhibited tumor property of Ishikawa cells in vivo. STAT3 bound to the promoter region of LDHB, and STAT3 silencing-induced effects were relieved after LDHB upregulation. LDHB interacted with and regulated MDH2 expression. Moreover, MDH2 overexpression rescued LDHB knockdown-induced effects on EC cell phenotypes. STAT3-activated LDHB promoted endometrial cancer cell malignancy by inducing MDH2 production.

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References

  1. Nagle, C. M., Crosbie, E. J., Brand, A., Obermair, A., Oehler, M. K., Quinn, M., Leung, Y., Spurdle, A. B., & Webb, P. M. (2018). The association between diabetes, comorbidities, body mass index and all-cause and cause-specific mortality among women with endometrial cancer. Gynecologic Oncology, 150(1), 99–105. https://doi.org/10.1016/j.ygyno.2018.04.006

    Article  CAS  PubMed  Google Scholar 

  2. Aoki, Y., Kanao, H., Wang, X., Yunokawa, M., Omatsu, K., Fusegi, A., & Takeshima, N. (2020). Adjuvant treatment of endometrial cancer today. Japanese Journal of Clinical Oncology, 50(7), 753–765. https://doi.org/10.1093/jjco/hyaa071

    Article  PubMed  Google Scholar 

  3. Braun, M. M., Overbeek-Wager, E. A., & Grumbo, R. J. (2016). Diagnosis and management of endometrial cancer. American Family Physician, 93(6), 468–474.

    PubMed  Google Scholar 

  4. Siegel, R. L., Miller, K. D., Fuchs, H. E., & Jemal, A. (2021). Cancer statistics, 2021. CA: A Cancer Journal for Clinicians, 71(1), 7–33. https://doi.org/10.3322/caac.21654

    Article  PubMed  Google Scholar 

  5. Yen, T. T., Wang, T. L., Fader, A. N., Shih, I. M., & Gaillard, S. (2020). Molecular classification and emerging targeted therapy in endometrial cancer. International Journal of Gynecological Pathology, 39(1), 26–35. https://doi.org/10.1097/pgp.0000000000000585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Urbańska, K., & Orzechowski, A. (2019). Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms20092085

    Article  PubMed  PubMed Central  Google Scholar 

  7. Leiblich, A., Cross, S. S., Catto, J. W., Phillips, J. T., Leung, H. Y., Hamdy, F. C., & Rehman, I. (2006). Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene, 25(20), 2953–2960. https://doi.org/10.1038/sj.onc.1209262

    Article  CAS  PubMed  Google Scholar 

  8. Li, C., Chen, Y., Bai, P., Wang, J., Liu, Z., Wang, T., & Cai, Q. (2016). LDHB may be a significant predictor of poor prognosis in osteosarcoma. American Journal of Translational Research, 8(11), 4831–4843.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Cui, J., Quan, M., Jiang, W., Hu, H., Jiao, F., Li, N., Jin, Z., Wang, L., Wang, Y., & Wang, L. (2015). Suppressed expression of LDHB promotes pancreatic cancer progression via inducing glycolytic phenotype. Medical Oncology, 32(5), 143. https://doi.org/10.1007/s12032-015-0589-8

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, D., & Yang, N. (2019). MiR-335-5p inhibits cell proliferation, migration and invasion in colorectal cancer through downregulating LDHB. Journal of B.U.ON., 24(3), 1128–1136.

    PubMed  Google Scholar 

  11. Frank, A. C., Raue, R., Fuhrmann, D. C., Sirait-Fischer, E., Reuse, C., Weigert, A., Lütjohann, D., Hiller, K., Syed, S. N., & Brüne, B. (2021). Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment. Theranostics, 11(15), 7570–7588. https://doi.org/10.7150/thno.58380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Darnell, J. E., Jr., Kerr, I. M., & Stark, G. R. (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 264(5164), 1415–1421. https://doi.org/10.1126/science.8197455

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Lee, H., Jeong, A. J., & Ye, S. K. (2019). Highlighted STAT3 as a potential drug target for cancer therapy. BMB Reports, 52(7), 415–423. https://doi.org/10.5483/BMBRep.2019.52.7.152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang, J. M., Jiang, J. Y., Zhang, D. L., Du, X., Wu, T., & Du, Z. X. (2021). HYOU1 facilitates proliferation, invasion and glycolysis of papillary thyroid cancer via stabilizing LDHB mRNA. Journal of Cellular and Molecular Medicine, 25(10), 4814–4825. https://doi.org/10.1111/jcmm.16453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fu, D., Li, J., Wei, J., Zhang, Z., Luo, Y., Tan, H., & Ren, C. (2018). HMGB2 is associated with malignancy and regulates Warburg effect by targeting LDHB and FBP1 in breast cancer. Cell Communication and Signaling: CCS, 16(1), 8. https://doi.org/10.1186/s12964-018-0219-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Capaci, V., Arrigoni, G., Monasta, L., Aloisio, M., Rocca, G., Di Lorenzo, G., Licastro, D., Romano, F., Ricci, G., & Ura, B. (2023). Phospho-DIGE Identified Phosphoproteins Involved in Pathways Related to Tumour Growth in Endometrial Cancer. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms241511987

    Article  PubMed  PubMed Central  Google Scholar 

  17. Fatma, H., Maurya, S. K., & Siddique, H. R. (2022). Epigenetic modifications of c-MYC: Role in cancer cell reprogramming, progression and chemoresistance. Seminars in Cancer Biology, 83, 166–176. https://doi.org/10.1016/j.semcancer.2020.11.008

    Article  CAS  PubMed  Google Scholar 

  18. Liu, H., Zeng, Z., Wang, S., Li, T., Mastriani, E., Li, Q. H., Bao, H. X., Zhou, Y. J., Wang, X., Liu, Y., Liu, W., Hu, S., Gao, S., Yu, M., Qi, Y., Shen, Z., Wang, H., Gao, T., Dong, L., … Liu, S. L. (2017). Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9. Cancer Biology & Therapy, 18(12), 990–999. https://doi.org/10.1080/15384047.2017.1394542

    Article  CAS  Google Scholar 

  19. Vandel, J., Cassan, O., Lèbre, S., Lecellier, C. H., & Bréhélin, L. (2019). Probing transcription factor combinatorics in different promoter classes and in enhancers. BMC Genomics, 20(1), 103. https://doi.org/10.1186/s12864-018-5408-0

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wang, H., Huo, X., Yang, X. R., He, J., Cheng, L., Wang, N., Deng, X., Jin, H., Wang, N., Wang, C., Zhao, F., Fang, J., Yao, M., Fan, J., & Qin, W. (2017). STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. Molecular Cancer, 16(1), 136. https://doi.org/10.1186/s12943-017-0680-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, W., Gong, M., Zhang, W., Mo, J., Zhang, S., Zhu, Z., Wang, X., Zhang, B., Qian, W., Wu, Z., Ma, Q., & Wang, Z. (2022). Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling. Cell Death & Disease, 13(7), 630. https://doi.org/10.1038/s41419-022-05082-3

    Article  CAS  Google Scholar 

  22. Wang, L., Zhao, Q. F., Yang, B. B., Liang, H. J., Zhang, X. E., Zhang, X. Y., Yang, W. J., Guo, Z. Y., Xu, X., Tian, F., & Wu, Q. H. (2023). STAT3-EphA7 axis contributes to the progression of esophageal squamous cell carcinoma. Acta Oncologica, 62(12), 1757–1766. https://doi.org/10.1080/0284186x.2023.2259601

    Article  CAS  PubMed  Google Scholar 

  23. Hu, M., Yang, J., Xu, Y., & Liu, J. (2022). MDH1 and MDH2 Promote Cell Viability of Primary AT2 Cells by Increasing Glucose Uptake. Computational and Mathematical Methods in Medicine, 2022, 2023500. https://doi.org/10.1155/2022/2023500

    Article  PubMed  PubMed Central  Google Scholar 

  24. Pei, X., Li, K. Y., Shen, Y., Li, J. T., Lei, M. Z., Fang, C. Y., Lu, H. J., Yang, H. J., Wen, W., Yin, M., Qu, J., & Lei, Q. Y. (2022). Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth. Science China Life Sciences, 65(10), 2017–2030. https://doi.org/10.1007/s11427-021-2048-2

    Article  CAS  PubMed  Google Scholar 

  25. Lo, Y. W., Lin, S. T., Chang, S. J., Chan, C. H., Lyu, K. W., Chang, J. F., May, E. W., Lin, D. Y., Chou, H. C., & Chan, H. L. (2015). Mitochondrial proteomics with siRNA knockdown to reveal ACAT1 and MDH2 in the development of doxorubicin-resistant uterine cancer. Journal of Cellular and Molecular Medicine, 19(4), 744–759. https://doi.org/10.1111/jcmm.12388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. He, D., Xin, T., Pang, B., Sun, J., Liu, Z. H., Qin, Z., Ji, X. S., Yang, F., Wei, Y. B., Wang, Z. X., Gao, J. J., Pang, Q., & Liu, Q. (2022). A novel lncRNA MDHDH suppresses glioblastoma multiforme by acting as a scaffold for MDH2 and PSMA1 to regulate NAD+ metabolism and autophagy. Journal of Experimental & Clinical Cancer Research, 41(1), 349. https://doi.org/10.1186/s13046-022-02543-7

    Article  CAS  Google Scholar 

  27. Zhuang, Y., Xiang, J., Bao, W., Sun, Y., Wang, L., Tan, M., He, Y., & Xi, X. (2017). MDH2 stimulated by estrogen-GPR30 pathway down-regulated PTEN expression promoting the proliferation and invasion of cells in endometrial cancer. Translational Oncology, 10(2), 203–210. https://doi.org/10.1016/j.tranon.2017.01.009

    Article  PubMed  PubMed Central  Google Scholar 

  28. Li, Y., Liang, J., Tian, X., Chen, Q., Zhu, L., Wang, H., Liu, Z., Dai, X., Bian, C., & Sun, C. (2023). Intermittent fasting promotes adipocyte mitochondrial fusion through Sirt3-mediated deacetylation of Mdh2. British Journal of Nutrition, 130(9), 1473–1486. https://doi.org/10.1017/s000711452300048x

    Article  CAS  PubMed  Google Scholar 

  29. Chen, C. L., Hsieh, F. C., Lieblein, J. C., Brown, J., Chan, C., Wallace, J. A., Cheng, G., Hall, B. M., & Lin, J. (2007). Stat3 activation in human endometrial and cervical cancers. British Journal of Cancer, 96(4), 591–599. https://doi.org/10.1038/sj.bjc.6603597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

This work was supported by the project of Hubei Provincial Health Committee: Effect of LDHB-mediated abnormal lactic acid metabolism on type I endometrial carcinoma (WJ2023M044).

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  1. Li Shen and Juan Wang have contributed equally to this paper.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, 430070, Hubei, China

    Li Shen & Juan Wang

  2. Department of Rehabilitation, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, 430070, Hubei, China

    Yanxia Li, Cuizhen Sun, Minjie Teng & Xiaohe Ye

  3. Department of Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 39 Yanhu Road, East Lake Eco-Tourism Scenic Spot, Wuhan City, 430070, Hubei, China

    Xiaomin Feng

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Shen, L., Wang, J., Li, Y. et al. Transcription Factor STAT3-Activated LDHB Promotes Tumor Properties of Endometrial Cancer Cells by Inducing MDH2 Expression. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01067-z

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