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Although immune checkpoint inhibitors (ICIs) have achieved unprecedented success in dMMR tumors, pMMR tumors accounting for 85% of colorectal cancer (CRC) cases remain unresponsive. Lactate dehydrogenase A (LDH-A) is the rate-limiting enzyme that catalyzes the transformation of pyruvate to lactate in the process of glycolysis. We investigated the relationship between LDH-A and dMMR with the purpose of exploring the treatment strategy for pMMR CRC patients. We here show that LDH-A can promote the proliferation of dMMR and pMMR CRC cells by positively regulating MMR proteins both in vitro and in vivo. LDH-A inhibition can improve the efficacy of PD-1 blockade in a pMMR CRC xenograft model. A statistical analysis of 186 CRC specimens showed a significant correlation between LDH-A and dMMR status. Moreover, patients with both low LDH-A expression and dMMR exhibited better disease-free survival compared with patients with other combinations. The close correlation of LDH-A and dMMR may offer a promising therapeutic strategy in which the combination of LDH-A inhibitor and ICIs may improve the clinical benefit for pMMR CRC patients.

Titel:	LDH-A negatively regulates dMMR in colorectal cancer.
Autor/in / Beteiligte Person:	Zhang, Y ; Li, J ; Wang, B ; Chen, T ; Chen, Y ; Ma, W
Link:	Full Text Finder (Volltext)
Zeitschrift:	Cancer science, Jg. 112 (2021-08-01), Heft 8, S. 3050-3063
Veröffentlichung:	2005- : Oxford : Wiley Publishing on behalf of the Japanese Cancer Association ; <i>Original Publication</i>: Tokyo : Japanese Cancer Association, c2003-, 2021
Medientyp:	academicJournal
ISSN:	1349-7006 (electronic)
DOI:	10.1111/cas.15020
Schlagwort:	Cell Line, Tumor Cell Proliferation Colorectal Neoplasms genetics Colorectal Neoplasms metabolism Female Gene Expression Regulation, Neoplastic HCT116 Cells Humans L-Lactate Dehydrogenase genetics Lung Neoplasms genetics Lung Neoplasms metabolism Male Middle Aged Neoplasm Transplantation Prognosis Survival Analysis Colorectal Neoplasms pathology DNA Mismatch Repair L-Lactate Dehydrogenase metabolism Lung Neoplasms pathology Lung Neoplasms secondary
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Cancer Sci] 2021 Aug; Vol. 112 (8), pp. 3050-3063. <i>Date of Electronic Publication: </i>2021 Jul 04. MeSH Terms: DNA Mismatch Repair* ; Colorectal Neoplasms / pathology ; L-Lactate Dehydrogenase / metabolism ; Lung Neoplasms / pathology ; Lung Neoplasms / secondary ; Cell Line, Tumor ; Cell Proliferation ; Colorectal Neoplasms / genetics ; Colorectal Neoplasms / metabolism ; Female ; Gene Expression Regulation, Neoplastic ; HCT116 Cells ; Humans ; L-Lactate Dehydrogenase / genetics ; Lung Neoplasms / genetics ; Lung Neoplasms / metabolism ; Male ; Middle Aged ; Neoplasm Transplantation ; Prognosis ; Survival Analysis References: Anticancer Res. 2018 Nov;38(11):6399-6404. (PMID: 30396964) ; Science. 2015 Apr 3;348(6230):124-8. (PMID: 25765070) ; Lancet. 2018 May 26;391(10135):2128-2139. (PMID: 29754777) ; Immunity. 2016 Mar 15;44(3):698-711. (PMID: 26982367) ; Cancer Immunol Immunother. 2012 Jul;61(7):1019-31. (PMID: 22146893) ; Lancet Oncol. 2017 Sep;18(9):1182-1191. (PMID: 28734759) ; Annu Rev Immunol. 2004;22:329-60. (PMID: 15032581) ; Science. 2007 Dec 21;318(5858):1917-20. (PMID: 18029452) ; N Engl J Med. 2015 Jun 25;372(26):2509-20. (PMID: 26028255) ; Cancer Sci. 2021 Aug;112(8):3050-3063. (PMID: 34110068) ; Cell. 2015 Jan 15;160(1-2):48-61. (PMID: 25594174) ; Science. 2013 Mar 29;339(6127):1546-58. (PMID: 23539594) ; Cell Metab. 2016 Nov 8;24(5):657-671. (PMID: 27641098) ; Int J Environ Res Public Health. 2016 Sep 08;13(9):. (PMID: 27618077) ; Cell Metab. 2016 Nov 8;24(5):649-650. (PMID: 27829133) ; Nature. 2014 Nov 27;515(7528):568-71. (PMID: 25428505) ; Nature. 2014 Nov 27;515(7528):563-7. (PMID: 25428504) ; J Immunother Cancer. 2014 Jul 15;2:23. (PMID: 25126421) ; Cancer Discov. 2015 Jan;5(1):43-51. (PMID: 25358689) ; Immunology. 2007 May;121(1):1-14. (PMID: 17386080) ; Oncogene. 2008 Oct 6;27(45):5894-903. (PMID: 18836470) ; J Clin Oncol. 2018 Mar 10;36(8):773-779. (PMID: 29355075) ; Cancer Res. 2012 Apr 1;72(7):1717-27. (PMID: 22337995) ; Int J Cancer. 2019 Apr 15;144(8):1941-1953. (PMID: 30350310) ; Nat Rev Gastroenterol Hepatol. 2019 Jun;16(6):361-375. (PMID: 30886395) ; J Biol Chem. 2005 Jul 1;280(26):24731-7. (PMID: 15860457) ; Nat Genet. 2006 Apr;38(4):431-40. (PMID: 16518401) ; Nature. 2008 Jul 31;454(7204):646-50. (PMID: 18594515) ; Biochem Biophys Res Commun. 2016 Jan 22;469(4):985-92. (PMID: 26721441) ; J Clin Oncol. 2020 Jun 20;38(18):2053-2061. (PMID: 32343640) ; PLoS One. 2018 Sep 24;13(9):e0203965. (PMID: 30248111) ; Nat Rev Mol Cell Biol. 2006 May;7(5):335-46. (PMID: 16612326) ; Nature. 1993 Sep 16;365(6443):274-6. (PMID: 8371783) ; Sci Transl Med. 2013 Aug 28;5(200):200ra116. (PMID: 23986400) ; Nature. 1993 Jun 10;363(6429):558-61. (PMID: 8505985) ; Science. 1993 May 7;260(5109):812-6. (PMID: 8484121) ; Front Immunol. 2014 Jul 29;5:360. (PMID: 25120546) Grant Information: HAB201818 Huai'an Science and Technology Bureau Contributed Indexing: Keywords: colorectal cancer; disease-free survival; lactate dehydrogenase A (LDH-A); mismatch-repair-deficient (dMMR); mismatch-repair-proficient (pMMR) Substance Nomenclature: EC 1.1.1.27 (L-Lactate Dehydrogenase) ; EC 1.1.1.27 (LDHA protein, human) Entry Date(s): Date Created: 20210610 Date Completed: 20210819 Latest Revision: 20210819 Update Code: 20231215 PubMed Central ID: PMC8353898

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LDH-A negatively regulates dMMR in colorectal cancer.