LINC01764 promotes colorectal cancer cells proliferation, metastasis, and 5-fluorouracil resistance by regulating glucose and glutamine metabolism via promoting c-MYC translation

Abstract

Few biomarkers are available for predicting chemotherapeutic response and prognosis in colorectal cancer (CRC). Long-noncoding RNAs (lncRNAs) are essential for CRC development and growth. Therefore, studying lncRNAs may reveal potential predictors of chemotherapy response and prognosis in CRC. LINC01764 was analyzed using datasets from Fudan University Shanghai Cancer Center’s advanced CRC patients’ RNA-seq and The Cancer Genome Atlas datasets. Gene set enrichment analysis was employed to detect related pathways. Cotransfection experiments, RNA pulldown assays, RNA-binding protein immunoprecipitation, protein synthesis activity, and dual-luciferase reporter assays were performed to determine interactions among LINC01764, hnRNPK, and c-MYC. High LINC01764 expression correlates with metastasis, a poor response to FOLFOX/XELOX chemotherapy, and a poor prognosis in CRC. LINC01764 enhance glycolysis and glutamine metabolism to promote CRC cells proliferation, metastasis, and 5-fluorouracil (5-FU) resistance. LINC01764 specifically binds to hnRNPK, facilitating its interaction with c-MYC mRNA and promoting internal ribosome entry site (IRES)-dependent translation of c-MYC, thereby exerting oncogenic effects. LINC01764 induced 5-FU chemoresistance by upregulating the c-MYC, glucose, and glutamine metabolism pathways, which downregulated UPP1, crucial for activating 5-FU. Conclusively, LINC01764 promotes CRC progression and 5-FU resistance through hnRNPK-mediated-c-MYC IRES-dependent translational regulation, which suggests its potential as a predictor of CRC chemotherapy response and prognosis.

Keywords

5-FU resistance / CRC / lncRNA / metastasis / proliferation

References

[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: gLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin. 2021; 71(3): 209-249.

[2] Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. Jama. 2021; 325(7): 669.

[3] Fan A, Wang B, Wang X, et al. Immunotherapy in colorectal cancer: current achievements and future perspective. Int J Biol Sci. 2021; 17(14): 3837-3849.

[4] Zhang X, Duan R, Wang Y, et al. FOLFIRI (folinic acid, fluorouracil, and irinotecan) increases not efficacy but toxicity compared with single-agent irinotecan as a second-line treatment in metastatic colorectal cancer patients: a randomized clinical trial. Ther Adv Med Oncol. 2022; 14: 175883592110687.

[5] Huang M, Yang Y, Li Q, et al. Induction chemotherapy followed by primary tumor resection did not bring survival benefits in colon cancer patients with asymptomatic primary lesion and synchronous unresectable metastases. Front Oncol. 2022; 12: 747124.

[6] Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017; 170(3): 548-563. e16.

[7] Ogunwobi OO, Mahmood F, Akingboye A. Biomarkers in colorectal cancer: current research and future prospects. Int J Mol Sci. 2020; 21(15): 5311.

[8] Peng WX, Koirala P, Mo YY. LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 2017; 36(41): 5661-5667.

[9] Beermann J, Piccoli MT, Viereck J, Thum T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016; 96(4): 1297-1325.

[10] Schmitz SU, Grote P, Herrmann BG. Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci. 2016; 73(13): 2491-2509.

[11] Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: a new paradigm. Cancer Res. 2017; 77(15): 3965-3981.

[12] Xing C, gang SunS, Yue ZQ, Bai F. Role of lncRNA LUCAT1 in cancer. Biomed Pharmacother. 2021; 134: 111158.

[13] Shi K, Yang S, Chen C, et al. RNA methylation-mediated LINC01559 suppresses colorectal cancer progression by regulating the miR-106b-5p/PTEN axis. Int J Biol Sci. 2022; 18(7): 3048-3065.

[14] Chen S, Shen X. Long noncoding RNAs: functions and mechanisms in colon cancer. Mol Cancer. 2020; 19(1): 167.

[15] Tan Y, Lin J, Li T, Li J, Xu R, Ju H. LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer. Cancer Commun. 2021; 41(2): 109-120.

[16] Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012; 81(1): 145-166.

[17] Liang WC, Fu WM, Wong CW, et al. The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget. 2015; 6(26): 22513-22525.

[18] Ferrè F, Colantoni A, Helmer-Citterich M. Revealing protein–lncRNA interaction. Brief Bioinform. 2016; 17(1): 106-116.

[19] Li C, Zhang G, Zhao L, Ma Z, Chen H. Metabolic reprogramming in cancer cells: glycolysis, glutaminolysis, and Bcl-2 proteins as novel therapeutic targets for cancer. World J Surg Oncol. 2015; 14(1): 15.

[20] Liberti MV, Locasale JW. The warburg effect: how does it benefit cancer cells?. Trends Biochem Sci. 2016; 41(3): 211-218.

[21] Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004; 4(11): 891-899.

[22] Bhattacharya B, Mohd Omar MF, Soong R. The warburg effect and drug resistance. Br J Pharmacol. 2016; 173(6): 970-979.

[23] Cao X, Fang L, Gibbs S, et al. Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother Pharmacol. 2007; 59(4): 495-505.

[24] Huang CY, Huang CY, Pai YC, et al. Glucose metabolites exert opposing roles in tumor chemoresistance. Front Oncol. 2019; 9: 1282.

[25] Shi H, Li K, Feng J, Zhang X. Overexpression of long non-coding RNA urothelial carcinoma associated 1 causes paclitaxel (Taxol) resistance in colorectal cancer cells by promoting glycolysis. J Chemother. 2021; 33(6): 409-419.

[26] Gan L, Li Q, Nie W, et al. PROX1-mediated epigenetic silencing of SIRT3 contributes to proliferation and glucose metabolism in colorectal cancer. Int J Biol Sci. 2023; 19(1): 50-65.

[27] Evans JR, Mitchell SA, Spriggs KA, et al. Members of the poly (rC) binding protein family stimulate the activity of the c-myc internal ribosome entry segment in vitro and in vivo. Oncogene. 2003; 22(39): 8012-8020.

[28] Zhang J, Ren P, Xu D, et al. Human UTP14a promotes colorectal cancer progression by forming a positive regulation loop with c-myc. Cancer Lett. 2019; 440-441: 106-115.

[29] Kim JW, Gao P, Liu YC, Semenza GL, Dang CV. Hypoxia-inducible factor 1 and dysregulated c-myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol. 2007; 27(21): 7381-7393.

[30] Osthus RC, Shim H, Kim S, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-myc. J Biol Chem. 2000; 275(29): 21797-21800.

[31] Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016; 135(8): 851-867.

[32] Gallardo M, Hornbaker MJ, Zhang X, Hu P, Bueso-Ramos C, Post SM. Aberrant hnRNP K expression: all roads lead to cancer. Cell Cycle. 2016; 15(12): 1552-1557.

[33] Barboro P, Ferrari N, Balbi C. Emerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression. Cancer Lett. 2014; 352(2): 152-159.

[34] Zhu S, Wang Z, Xu J. Connecting versatile lncRNAs with heterogeneous nuclear ribonucleoprotein K and pathogenic disorders. Trends Biochem Sci. 2019; 44(9): 733-736.

[35] Xu Y, Wu W, Han Q, et al. New insights into the interplay between non-coding RNAs and RNA-binding protein HnRNPK in regulating cellular functions. Cells. 2019; 8(1): 62.

[36] Zhang Z, Zhou C, Chang Y, et al. Long non-coding RNA CASC11 interacts with hnRNP-K and activates the WNT/β-catenin pathway to promote growth and metastasis in colorectal cancer. Cancer Lett. 2016; 376(1): 62-73.

[37] Lang KJD, Kappel A, Goodall GJ. Hypoxia-inducible factor-1α mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Wickens MP, ed. Mol Biol Cell. 2002; 13(5): 1792-1801.

[38] Braunstein S, Karpisheva K, Pola C, et al. A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol Cell. 2007; 28(3): 501-512.

[39] Le Quesne JP, Spriggs KA, Bushell M, Willis AE. Dysregulation of protein synthesis and disease. J Pathol. 2010; 220(2): 140-151.

[40] Halaby MJ, Yang DQ. p53 translational control: a new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics. Gene. 2007; 395(1-2): 1-7.

[41] Holcik M, Lefebvre C, Yeh C, Chow T, Korneluk RG. A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection. Nat Cell Biol. 1999; 1(3): 190-192.

[42] Stoneley M, Paulin FE, Quesne JPL, Chappell SA, Willis AE. C-myc 5’ untranslated region contains an internal ribosome entry segment. Oncogene. 1998; 16(3): 423-428.

[43] Shi Y, Sun F, Cheng Y, et al. Critical role for cap-independent c-MYC translation in progression of multiple myeloma. Mol Cancer Ther. 2022; 21(4): 502-510.

[44] Xiao J, Sun Q, Ding L, et al. The c-MYC–BMI1 axis is essential for SETDB1-mediated breast tumourigenesis. The Journal of Pathology. 2018; 246(1): 89-102.

[45] Li M, Thorne RF, Shi R, et al. DDIT3 directs a dual mechanism to balance glycolysis and oxidative phosphorylation during glutamine deprivation. Adv Sci. 2021; 8(11): 2003732.

[46] Son J, Lyssiotis CA, Ying H, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013; 496(7443): 101-105.

[47] Wong CC, Xu J, Bian X, et al. In colorectal cancer cells with mutant KRAS, SLC25A22-mediated glutaminolysis reduces DNA demethylation to increase WNT signaling, stemness, and drug resistance. Gastroenterology. 2020; 159(6): 2163-2180. e6.

[48] Amaya ML, Inguva A, Pei S, et al. The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation. Blood. 2022; 139(4): 584-596.

[49] Bhardwaj V, He J, Jain A. Glutamine stabilizes myc via alpha-ketoglutarate and regulates paclitaxel sensitivity. Med Oncol (Northwood, London, England). 2022; 39(12): 227.

[50] Zhao Y, Feng X, Chen Y, et al. 5-fluorouracil enhances the antitumor activity of the glutaminase inhibitor CB-839 against PIK3CA-mutant colorectal cancers. Cancer Res. 2020; 80(21): 4815-4827.

[51] Liu X, Su K, Sun X, et al. Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating wnt/β-catenin pathway. J Exp Clin Cancer Res. 2021; 40(1): 132.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.