Abstract
BackgroundResistance 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.MethodsChemo-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.ResultsIn 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.ConclusionIn 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.
Highlights
Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC)
Lnc‐RP11‐536 K7.3 was highly expressed in oxaliplatin‐resistant organoids of CC patients and predicted worse prognosis In order to investigate mechanisms of resistance to oxaliplatin through a model with a superior genetic and phenotypic recapitulation, chemo-resistant and -sensitive organoids derived from CC patients were established
IHC revealed that the expressions of CK20 and β-catenin were higher in oxaliplatin-resistant organoids compared with oxaliplatin-sensitive organoids, indicating that oxaliplatin-resistant organoids behaved more aggressively (Fig. S1E)
Summary
Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Oxaliplatin-based chemotherapy is recommended for locally advanced or metastatic CC [2, 3]. Acquisition of resistance to chemotherapy results in therapy failure and disease progression in a number of CC patients. Great efforts have been dedicated to reveal the mechanism of resistance acquisition of oxaliplatin and propose some interventional strategies [4, 5]. The cause of resistance acquisition of oxaliplatin remains elusive. It is highly essential to elucidate the precise mechanisms of resistance to oxaliplatin, identify effective biomarkers for predicting oxaliplatin response, and develop targeted therapies for minimizing resistance to oxaliplatin in CC patients
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