Integrative Bioinformatics Reveals the Lactate Dehydrogenase B (LDHB) Significance in Colon Adenocarcinoma
Abstract
Background: Lactate dehydrogenase B (LDHB), a typical oxidoreductase for converting lactate to pyruvate in the glycolysis process, takes a complex function in the progression of cancer cells. Even so, the profile of LDHB relevance in colon adenocarcinoma (COAD) remains ambiguous. Hence this study analyzed the expression and co-expression profile of LDHB, and its immune correlation in COAD.
Materials and method: The mRNA expression and co-expression of LDHB in COAD were retrieved from UALCAN. The immune infiltration levels of LDHB from B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in COAD were assessed using the TIMER database. For assessing gene ontology and the KEGG pathway, DAVID v6.8 was utilized. The protein-protein interaction of LDHB-correlated genes was analyzed using STRINGDB and Cytoscape.
Results: Significantly high expression of LDHB in COAD was spotted in several sample types and associated with a poor overall survival rate. Further, LDHB corresponded to the level of CD4+, macrophages, and myeloid-derived suppressor cell (MDSC) immune infiltrating cells. The co-expression of LDHB was associated with several essential genes for cell cycle progression.
Conclusion: The findings of this study indicate an upcoming involvement of LDHB in COAD tumorigenesis and prognosis. Additionally, this study highlights the immune correlation of LDHB in COAD as preliminary data in developing diagnosis and treatment with a novel immune checkpoint in COAD.
Keywords: lactate dehydrogenase, colon adenocarcinoma, expression, survival, immune
References
Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023; 73(3): 233-54, CrossRef.
Zessner-Spitzenberg J, Thomas AL, Krett NL, Jung B. TGFβ and activin A in the tumor microenvironment in colorectal cancer. Gene Rep. 2019; 17: 100501, CrossRef.
Brown RE, Short SP, Williams CS. Colorectal cancer and metabolism. Curr Colorectal Cancer Rep. 2018; 14(6): 226-41, CrossRef.
Mishra D, Banerjee D. Lactate dehydrogenases as metabolic links between tumor and stroma in the tumor microenvironment. Cancers. 2019; 11(6): 750, CrossRef.
Nagamine A, Araki T, Nagano D, Miyazaki M, Yamamoto K. L-Lactate dehydrogenase B may be a predictive marker for sensitivity to anti-EGFR monoclonal antibodies in colorectal cancer cell lines. Oncol Lett. 2019; 17(5): 4710-6, CrossRef.
Clifton KK, Ma CX, Fontana L, Peterson LL. Intermittent fasting in the prevention and treatment of cancer. CA A Cancer J Clin. 2021; 71(6): 527-46, CrossRef.
Su Y, Lu K, Huang Y, Zhang J, Sun X, Peng J, et al. Targeting Warburg effect to rescue the suffocated photodynamic therapy: A cancer-specific solution. Biomaterials. 2023; 294: 122017, CrossRef.
Wang Y, Nie H, Liao Z, He X, Xu Z, Zhou J, et al. Expression and Clinical Significance of Lactate Dehydrogenase A in Colon Adenocarcinoma. Front Oncol. 2021; 11: 700795, CrossRef.
Zou Z, Chai Y, Li Q, Lin X, He Q, Xiong Q. Establishment of lactate-metabolism-related signature to predict prognosis and immunotherapy response in patients with colon adenocarcinoma. Front Oncol. 2022; 12: 958221, CrossRef.
Macharia JM, Kaposztas Z, Varjas T, Budán F, Zand A, Bodnar I, et al. Targeted lactate dehydrogenase genes silencing in probiotic lactic acid bacteria: A possible paradigm shift in colorectal cancer treatment? Biomed Pharmacother. 2023; 160: 114371, CrossRef.
Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020; 48(W1): W509-14, CrossRef.
Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, et al. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017; 19(8): 649-58, CrossRef.
McCleland ML, Adler AS, Deming L, Cosino E, Lee L, Blackwood EM, et al. Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. Clin Cancer Res. 2013; 19(4): 773-84, CrossRef.
Deng H, Gao Y, Trappetti V, Hertig D, Karatkevich D, Losmanova T, et al. Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage. Cell Mol Life Sci. 2022; 79(8): 445, CrossRef.
Chen R, Zhou X, Yu Z, Liu J, Huang G. Low expression of LDHB correlates with unfavorable survival in hepatocellular carcinoma: Strobe-compliant article. Medicine. 2015; 94(39): e1583, CrossRef.
Nzinga M, Mazzio EA, Bauer D, Flores-Rozas H, Soliman KFA. Stable shRNA silencing of lactate dehydrogenase A (LDHA) in human MDA-MB-231 breast cancer cells fails to alter lactic acid production, glycolytic activity, ATP or survival. Anticancer Res. 2017; 37(3): 1205-12, CrossRef.
Sanford JD, Jin A, Grois GA, Zhang Y. A role of cytoplasmic p53 in the regulation of metabolism shown by bat-mimicking p53 NLS mutant mice. Cell Reports. 2023; 42(1): 111920, CrossRef.
Taebi R, Mirzaiey MR, Mahmoodi M, Khoshdel A, Fahmidehkar MA, Mohammad-Sadeghipour M, et al. The effect of Curcuma longa extract and its active component (curcumin) on gene expression profiles of lipid metabolism pathway in liver cancer cell line (HepG2). Gene Reports. 2020; 18: 100581, CrossRef.
Kocianova E, Piatrikova V, Golias T. Revisiting the Warburg effect with focus on lactate. Cancers. 2022; 14(24): 6028, CrossRef.
Luo C, Cen S, Ding G, Wu W. Mucinous colorectal adenocarcinoma: clinical pathology and treatment options. Cancer Commun. 2019; 39(1): 13, CrossRef.
Wu G, Yuan S, Chen Z, Chen G, Fan Q, Dong H, et al. The KLF14 transcription factor regulates glycolysis by downregulating LDHB in colorectal cancer. Int J Biol Sci. 2019; 15(3): 628-35, CrossRef.
Aday U, Böyük A, Akkoç H. The prognostic significance of serum lactate dehydrogenase-to-albumin ratio in colorectal cancer. Ann Surg Treat Res. 2020; 99(3): 161-70, CrossRef.
Shi L, Yan H, An S, Shen M, Jia W, Zhang R, et al. SIRT 5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol Oncol. 2019; 13(2): 358-75, CrossRef.
Zhang W, Tong D, Liu F, Li D, Li J, Cheng X, et al. RPS7 inhibits colorectal cancer growth via decreasing HIF-1α-mediated glycolysis. Oncotarget. 2016; 7(5): 5800-14, CrossRef.
Wang Y, Wang F, He J, Du J, Zhang H, Shi H, et al. miR-30a-3p targets MAD2L1 and regulates proliferation of gastric cancer cells. Onco Targets Ther. 2019; 12: 11313-24, CrossRef.
Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep. 2015; 42(4): 841-51, CrossRef.
Leal-Esteban LC, Fajas L. Cell cycle regulators in cancer cell metabolism. Biochim Biophys Acta Mol Basis Dis. 2020; 1866(5): 165715, CrossRef.
Driscoll DL, Chakravarty A, Bowman D, Shinde V, Lasky K, Shi J, et al. Plk1 inhibition causes post-mitotic DNA damage and senescence in a range of human tumor cell lines. PLoS One. 2014; 9(11): e111060, CrossRef.
Nguyen TTT, Shang E, Westhoff MA, Karpel-Massler G, Siegelin MD. Therapeutic drug-induced metabolic reprogramming in glioblastoma. Cells. 2022; 11(19): 2956, CrossRef.
Zhou H, Wang Y, Zhang Z, Xiong L, Liu Z, Wen Y. A novel prognostic gene set for colon adenocarcinoma relative to the tumor microenvironment, chemotherapy, and immune therapy. Front Genet. 2023; 13: 975404, CrossRef.
Decking SM, Bruss C, Babl N, Bittner S, Klobuch S, Thomas S, et al. LDHB overexpression can partially overcome T cell inhibition by lactic acid. Int J Mol Sci. 2022; 23(11): 5970, CrossRef.
Zhong X, He X, Wang Y, Hu Z, Huang H, Zhao S, et al. Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications. J Hematol Oncol. 2022; 15(1): 160, CrossRef.
Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013; 140(15): 3079-93, CrossRef.
Li B, Zhu HB, Song GD, Cheng JH, Li CZ, Zhang YZ, et al. Regulating the CCNB1 gene can affect cell proliferation and apoptosis in pituitary adenomas and activate epithelial-to-mesenchymal transition. Oncol Lett. 2019; 18(5): 4651-8, CrossRef.
Wang Z, Wan L, Zhong J, Inuzuka H, Liu P, Sarkar FH, et al. Cdc20: A potential novel therapeutic target for cancer treatment. Curr Pharm Des. 2013; 19(18): 3210-4, CrossRef.
Gan Y, Li Y, Li T, Shu G, Yin G. CCNA2 acts as a novel biomarker in regulating the growth and apoptosis of colorectal cancer. Cancer Manag Res. 2018; 10: 5113-24, CrossRef.
Liu X, Zhang Y, Wu S, Xu M, Shen Y, Yu M, et al. Palmatine induces G2/M phase arrest and mitochondrial-associated pathway apoptosis in colon cancer cells by targeting AURKA. Biochemical Pharmacology. 2020; 175: 113933, CrossRef.
An X, Xu F, Luo R, Zheng Q, Lu J, Yang Y, et al. The prognostic significance of topoisomerase II alpha protein in early stage luminal breast cancer. BMC Cancer. 2018; 18(1): 331, CrossRef.
Zheng F, Yue C, Li G, He B, Cheng W, Wang X, et al. Nuclear AURKA acquires kinase-independent transactivating function to enhance breast cancer stem cell phenotype. Nat Commun. 2016; 7(1): 10180, CrossRef.
Yan HC, Xiang C. Aberrant expression of BUB1B contributes to the progression of thyroid carcinoma and predicts poor outcomes for patients. J Cancer. 2022; 13(7): 2336–51, CrossRef.
DOI: https://doi.org/10.21705/mcbs.v7i2.346
Copyright (c) 2023 Cell and BioPharmaceutical Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
Cell and BioPharmaceutical Institute
