Lactate Metabolism-Associated lncRNA Pairs: A Prognostic Signature to Reveal the Immunological Landscape and Mediate Therapeutic Response in Patients With Colon Adenocarcinoma

BACKGROUND: Lactate metabolism is critically involved in the tumor microenvironment (TME), as well as cancer progression. It is important to note, however, that lactate metabolism-related long non-coding RNAs (laRlncRNAs) remain incredibly understudied in colon adenocarcinoma (COAD). METHODS: A gene expression profile was obtained from the Cancer Genome Atlas (TCGA) database to identify laRlncRNA expression in COAD patients. A risk signature with prognostic value was identified from TCGA and Gene Expression Omnibus (GEO) cohort based on laRlncRNA pairs by the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) and functional experiments were carried out to verify the expression of laRlncRNAs in COAD. The relationship of laRlncRNA pairs with immune landscape as well as the sensitivity of different therapies was explored. RESULTS: In total, 2378 laRlncRNAs were identified, 1,120 pairs of which were studied to determine their prognostic validity, followed by a risk signature established based on the screened 5 laRlncRNA pairs. The laRlncRNA pairs-based signature provided a better overall survival (OS) prediction than other published signatures and functioned as a prognostic marker for COAD patients. According to the calculated optimal cut-off point, patients were divided into high- and low-risk groups. The OS of COAD patients in the high-risk group were significantly shorter than that of those in the low-risk group (P=4.252e-14 in the TCGA cohort and P=2.865-02 in the GEO cohort). Furthermore, it remained an effective predictor of survival in strata of gender, age, TNM stage, and its significance persisted after univariate and multivariate Cox regressions. Additionally, the risk signature was significantly correlated with immune cells infiltration, tumor mutation burden (TMB), microsatellite instability (MSI) as well as immunotherapeutic efficacy and chemotherapy sensitivity. Finally, one of the laRlncRNA, LINC01315, promotes proliferation and migration capacities of colon cancer cells. CONCLUSION: The newly identified laRlncRNAs pairs-based signature exhibits potential effects in predicting prognosis, deciphering patients’ immune landscape, and mediating sensitivity to immunotherapy and chemotherapy. Findings in our study may provide evidence for the role of laRlncRNAs pairs as novel prognostic biomarkers and potentially individualized therapy targets for COAD patients.