Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids

Abstract

Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.

NXPH4 Promotes Gemcitabine Resistance in Bladder Cancer by Enhancing Reactive Oxygen Species and Glycolysis Activation through Modulating NDUFA4L2

“…Recent studies have focused on the function of tumor metabolism, especially glycolysis, which is reported to play a role in promoting tumor drug resistance [ 10 , 11 , 12 ]. GEM-R bladder cancer cells showed increased glucose uptake, lactate production, and cell medium acidification ( Figure 5 D).…”

LncRNAs and CircRNAs in cancer

“…Chemo‐resistance of cancer cells is influenced by the activity of lncRNAs. 238 , 239 A recent study has revealed lncRNA ANRIL enhanced cancer resistance by promoting homologous recombination‐mediated DNA repair. 240 In addition, LINC00842 promoted malignancy through metabolic remodeling.…”

Noncoding RNAs in the Glycolysis of Ovarian Cancer

“…LINC00092 binds 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) and thus promotes malignant metastasis of OC by altering glycolysis and maintaining the local support function of cancer-associated fibroblasts (CAF) ( Zhao et al, 2017 ; Hashemipour et al, 2021 ). Li et al, revealed that CTSLP8 expression increases in chemoresistant tumor tissues, which promotes c-Myc expression and thus upregulates glycolysis by facilitating the binding of PKM2 to the c-Myc promoter region ( Li Q et al, 2021 ). Yang et al, demonstrated that LINC00035 promotes malignant progression of OC by regulating glycolysis and apoptosis through CEBPB-mediated SLC16A3 transcription ( Yang et al, 2021 ).…”

“…NcRNAs are involved in a variety of life activities such as regulation of gene expression, intracellular signaling and epigenetic modifications. Apart from participation in tumorigenesis, ncRNAs also account paramount role in the glycolytic process of tumors ( Li Q et al, 2021 ; Lu et al, 2021 ; Park et al, 2021 ; Razavi et al, 2021 ; Wang et al, 2021 ). This review summarizes the possible molecular mechanisms of ncRNAs in the process of glycolysis and potentially effective targeted therapies for OC.…”