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Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer

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Abstract

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

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Data Availability

The datasets used and/or analyzed during the current study are available in the NCBI Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/); GEO accession numbers: GSE24514, GSE49355, GSE68468, GSE77953, GSE110223, GSE3629, GSE4107, GSE4183, GSE5206, GSE9348, GSE13471, GSE15960, GSE21510, GSE23878, GSE32323, GSE33113, GSE37364, GSE41328, GSE62932, GSE110224, GSE81558, GSE113513, GSE54986, GSE75548, GSE106582, GSE21815, GSE35279, GSE15781, GSE20842, GSE25071, GSE28000, GSE41011, GSE44076, GSE47063, GSE62321, GSE87211, GSE103512, GSE115261, GSE126092, GSE141174, GSE156355), the cancer genome database (TCGA: COAD, READ; https://portal.gdc.cancer.gov), and the UCSC Xena (TCGA Colon and Rectal Cancer (COADREAD); https://xenabrowser.net/datapages/).

References

  1. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., et al. (2021). Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3):209–249.

  2. Keum, N., & Giovannucci, E. (2019). Global burden of colorectal cancer: Emerging trends, risk factors and prevention strategies. Nature Reviews Gastroenterology & Hepatology, 16(12), 713–732.

    Article  Google Scholar 

  3. He, T., Cheng, X., & Xing, C. (2021). The gut microbial diversity of colon cancer patients and the clinical significance. Bioengineered, 12(1), 7046–7060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yashiro, M. (2014). Ulcerative colitis-associated colorectal cancer. World Journal of Gastroenterology, 20(44), 16389–16397.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Johdi, N. A., & Sukor, N. F. (2020). Colorectal cancer immunotherapy: Options and strategies. Frontiers in Immunology, 11, 1624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Takei, S., Tanaka, Y., Lin, Y. T., Koyama, S., Fukuoka, S., Hara, H. et al. (2024). Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer. Journal for ImmunoTherapy of Cancer, 12(2).

  7. Guo, L., Wang, Y., Yang, W., Wang, C., Guo, T., Yang, J., et al. (2023). Molecular profiling provides clinical insights into targeted and immunotherapies as well as colorectal cancer prognosis. Gastroenterology, 165(2), 414–28.e7.

    Article  CAS  PubMed  Google Scholar 

  8. Emiloju, O. E., & Sinicrope, F. A. (2023). Neoadjuvant immune checkpoint inhibitor therapy for localized deficient mismatch repair colorectal cancer: A review. JAMA Oncology, 9(12), 1708–1715.

    Article  PubMed  Google Scholar 

  9. Tjader, N. P., & Toland, A. E. (2024). Immunotherapy for colorectal cancer: insight from inherited genetics. Trends Cancer.

  10. Zhu, Y. J., Li, X., Chen, T. T., Wang, J. X., Zhou, Y. X., Mu, X. L., et al. (2023). Personalised neoantigen-based therapy in colorectal cancer. Clinical and Translational Medicine, 13(11), e1461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Levy, S., Allerston, C. K., Liveanu, V., Habib, M. R., Gileadi, O., & Schuster, G. (2016). Identification of LACTB2, a metallo-β-lactamase protein, as a human mitochondrial endoribonuclease. Nucleic Acids Research, 44(4), 1813–1832.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chen, Q., Zheng, W., Zhu, L., Liu, H., Song, Y., Hu, S., et al. (2021). LACTB2 renders radioresistance by activating PINK1/Parkin-dependent mitophagy in nasopharyngeal carcinoma. Cancer Letters, 518, 127–139.

    Article  CAS  PubMed  Google Scholar 

  13. Liu, A. G., Zhong, J. C., Chen, G., He, R. Q., He, Y. Q., Ma, J., et al. (2020). Upregulated expression of SAC3D1 is associated with progression in gastric cancer. International Journal of Oncology, 57(1), 122–138.

    PubMed  PubMed Central  Google Scholar 

  14. Newman, A. M., Liu, C. L., Green, M. R., Gentles, A. J., Feng, W., Xu, Y., et al. (2015). Robust enumeration of cell subsets from tissue expression profiles. Nature Methods, 12(5), 453–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kanehisa, M. (2019). Toward understanding the origin and evolution of cellular organisms. Protein Science, 28(11), 1947–1951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kanehisa, M., Furumichi, M., Sato, Y., Ishiguro-Watanabe, M., & Tanabe, M. (2021). KEGG: Integrating viruses and cellular organisms. Nucleic Acids Research, 49(D1), D545–D551.

    Article  CAS  PubMed  Google Scholar 

  17. Sendoya, J. M., Iseas, S., Coraglio, M., Golubicki, M., Robbio, J., Salanova, R., et al. (2020). Pre-existing tumoral B cell infiltration and impaired genome maintenance correlate with response to chemoradiotherapy in locally advanced rectal cancer. Cancers (Basel)., 12(8), 2227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Largeot, A., Pagano, G., Gonder, S., Moussay, E., & Paggetti, J. (2019). The B-side of cancer immunity: The underrated tune. Cells., 8(5), 449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Krombach, J., Hennel, R., Brix, N., Orth, M., Schoetz, U., Ernst, A., et al. (2019). Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells. Oncoimmunology., 8(1), e1523097.

    Article  PubMed  Google Scholar 

  20. Cui, C., Wang, J., Fagerberg, E., Chen, P. M., Connolly, K. A., Damo, M., et al. (2021). Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. Cell, 184(25), 6101–18.e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Faubert, B., Solmonson, A., & DeBerardinis, R. J. (2020). Metabolic reprogramming and cancer progression. Science., 368(6487), 473.

    Article  Google Scholar 

  22. Xia, L., Oyang, L., Lin, J., Tan, S., Han, Y., Wu, N., et al. (2021). The cancer metabolic reprogramming and immune response. Molecular Cancer., 20(1), 28.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wu, Z., Zuo, M., Zeng, L., Cui, K., Liu, B., Yan, C., et al. (2021). OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development. EMBO Reports, 22(1), e50827.

    Article  CAS  PubMed  Google Scholar 

  24. Sun, X., Zhan, L., Chen, Y., Wang, G., He, L., Wang, Q., et al. (2018). Increased mtDNA copy number promotes cancer progression by enhancing mitochondrial oxidative phosphorylation in microsatellite-stable colorectal cancer. Signal Transduction and Targeted Therapy, 3, 8.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu, Y. D., Zhuang, X. P., Cai, D. L., Cao, C., Gu, Q. S., Liu, X. N., et al. (2021). Let-7a regulates EV secretion and mitochondrial oxidative phosphorylation by targeting SNAP23 in colorectal cancer. Journal of Experimental & Clinical Cancer Research, 40(1), 31.

    Article  CAS  Google Scholar 

  26. de la Cruz López, K. G., Toledo Guzmán, M. E., Sánchez, E. O., & García, C. A. (2019). mTORC1 as a regulator of mitochondrial functions and a therapeutic target in cancer. Frontiers in Oncology, 9, 1373.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Shi, H., Chapman, N. M., Wen, J., Guy, C., Long, L., Dhungana, Y., et al. (2019). Amino acids license kinase mTORC1 activity and Treg cell function via small G proteins Rag and Rheb. Immunity, 51(6), 1012–27.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wei, S., Dai, M., Zhang, C., Teng, K., Wang, F., Li, H., et al. (2021). KIF2C: A novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma. Protein & Cell, 12(10), 788–809.

    Article  CAS  Google Scholar 

  29. Wu, J., Yeung, S. J., Liu, S., Qdaisat, A., Jiang, D., Liu, W., et al. (2021). Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS. Signal Transduction and Targeted Therapy, 6(1), 188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Qiu, J., Zhang, S., Wang, P., Wang, H., Sha, B., Peng, H., et al. (2020). BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway. Cancer Medicine, 9(21), 8159–8172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang, T., Zhang, W. S., Wang, Z. X., Wu, Z. W., Du, B. B., Li, L. Y., et al. (2020). RAPTOR promotes colorectal cancer proliferation by inducing mTORC1 and upregulating ribosome assembly factor URB1. Cancer Medicine, 9(4), 1529–1543.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Clinical pathology support was provided by the Guangxi Key Laboratory of Medical Pathology.

Funding

This study was funded by the Guangxi Medical University Youth Science Foundation (GXMUYSF202423), the Guangxi Zhuang Autonomous Region Health Commission Self-Financed Scientific Research Project (Z-A20220415), and the Guangxi Natural Science Foundation Program (2015GXNSFAA139185).

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Authors and Affiliations

  1. Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuangyong RD 6, Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China

    Hui Li

  2. Department of Radiotherapy, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Rd, Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China

    Jia-Ying Wen

  3. Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Shuangyong RD 6, Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China

    Cui-Zhen Liu

  4. Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Shuangyong RD 6, Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China

    Ye-Ying Fang

  5. Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Shuangyong RD 6, Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China

    Yu-Ping Ye

  6. Department of Pathology, Redcross Hospital of Yulin City, Jinwang RD 1, Yuzhou District, Guangxi Zhuang Autonomous Region, Yulin, 537000, People’s Republic of China

    Da-Tong Zeng

  7. Department of Pathology, Hospital of Guangxi Liugang Medical Co., LTD./Guangxi Liuzhou Dingshun Forensic Expert Institute, Queershan RD 9, Liubei District, Guangxi Zhuang Autonomous Region, Liuzhou, 545002, People’s Republic of China

    Yan-Fang Pan

  8. Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, Daxuedong RD 166, Guangxi Zhuang Autonomous Region, Nanning, 530028, People’s Republic of China

    Zu-Xuan Chen

  9. Department of Toxicology, College of Pharmacy, Guangxi Medical University, Shuangyong RD 22, Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China

    Li-Min Liu

  10. Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Shuangyong RD 6, Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China

    Rui Song

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Contributions

HL and RS designed and directed this study. L-ML and J-YW were mainly involved in data collection and analysis. Experimental technical support provided by C-ZL, Y-YF, Y-PY, and D-TZ. Y-FP and Z-XC participated in manuscript writing. All authors discussed the results and approved the submission.

Corresponding author

Correspondence to Rui Song.

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Competing interests

The authors declare that they have no competing interests.

Ethical Approval and Consent to Participate

All procedures of this study followed the declaration of Helsinki. This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (No. 2022-KY-E-(047)). Written informed consent was obtained from all patients participating in this study.

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Li, H., Wen, JY., Liu, CZ. et al. Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01137-2

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