Role of lncSLCO1C1 in gastric cancer progression and resistance to oxaliplatin therapy

Abstract

Background Gastric carcinoma (GC) is one of the most deadly diseases due to tumour metastasis and resistance to therapy. Understanding the molecular mechanism of tumour progression and drug resistance will improve therapeutic efficacy and develop novel intervention strategies. Methods Differentially expressed long non‐coding RNAs (lncRNAs) in clinical specimens were identified by LncRNA microarrays and validated in different clinical cohorts by quantitative real‐time polymerase chain reaction (qRT‐PCR), in situ hybridisation and bioinformatics analysis. Biological functions of lncRNA were investigated by using cell proliferation assays, migration assays, xenograft tumour models and bioinformatics analysis. Effects of lncSLCO1C1 on GC cell survival were assessed by comet assays and immunofluorescence assays. Underlying molecular mechanisms were further explored by using a number of technologies including RNA pull‐down, mass spectrometry analysis, RNA immunoprecipitation, co‐immunoprecipitation, miRNA sequencing, luciferase reporter assays and molecular modelling. Results LncSLCO1C1 was highly upregulated in GC tissue samples and associated with GC patients’ poor overall survival. Overexpression of lncSLCO1C1 promoted proliferation and migration, whereas decreased lncSLCO1C1 expression produced the opposite effects. lncSLCO1C1 also mediated tumour resistance to chemotherapy with oxaliplatin by reducing DNA damage and increasing cell proliferation. Despite sequence overlapping between lncSLCO1C1 and PDE3A, alternations of PDE3A expression had no effect on the GC cell progression, indicating that lncSLCO1C1, not PDE3A, related with the progression of GC cells. Mechanistically, lncSLCO1C1 serves as a scaffold for the structure‐specific recognition protein 1 (SSRP1)/H2A/H2B complex and regulates the function of SSRP1 in reducing DNA damage. Meanwhile, lncSLCO1C1 functions as a sponge to adsorb miR‐204‐5p and miR‐211‐5p that target SSRP1 mRNA, and thus increases SSRP1 expression. Patients with high expressions of both lncSLCO1C1 and SSRP1 have poor overall survival, highlighting the role of lncSLCO1C1 in GC progression. Conclusions LncSLCO1C1 promotes GC progression by enhancing cell growth and preventing DNA damage via interacting and scaffolding the SSRP1/H2A/H2b complex and absorbing both miR‐211‐5p and miR‐204‐5p to increase SSRP1 expression.

Ultrasound-Assisted Extraction of Atractylodes chinensis (DC.) Koidz. Polysaccharides and the Synergistic Antigastric Cancer Effect in Combination with Oxaliplatin

“…Apatinib is an antiangiogenesis inhibitor, which can inhibit the formation of tumor neovascularization by binding to and inhibiting vascular cell growth factor receptor-2 so as to control tumor growth and become a third-line chemotherapy drug for gastric cancer . Compared with apatinib, Oxaliplatin (OXA) is a third-generation platinum-based anticancer drug containing diaminocyclohexane, which plays a DNA-targeted anticancer effect by inhibiting DNA replication and arresting the cell cycle in G 0 /G 1 phase . It is currently the first-line chemotherapy drug for gastric cancer in clinical practice, and it is cheaper and more applicable for most populations.…”

“… 38 Compared with apatinib, Oxaliplatin (OXA) is a third-generation platinum-based anticancer drug containing diaminocyclohexane, which plays a DNA-targeted anticancer effect by inhibiting DNA replication and arresting the cell cycle in G 0 /G 1 phase. 39 It is currently the first-line chemotherapy drug for gastric cancer in clinical practice, 6 and it is cheaper and more applicable for most populations. Current results showed that AKUs had a synergistic effect both on molecular targeted drugs and platinum anticancer drugs, suggesting that AKUs have the potential to be a sensitizer for a synergistic anticancer effect.…”

The Role of microRNAs in Regulating Cancer Cell Response to Oxaliplatin-Containing Regimens

“…68 LncSLCO1C1 increases the tumor resistance to treatment with oxaliplatin by reducing GC DNA damage and tumor cell proliferation and migration, while lncSLCO1C1 enhances SSRP1 expression in GC cells by acting as a sponge to absorb both miR-211-5p and miR-204-5p in the cytoplasm. 69…”

Oxaliplatin-Loaded Mil-100(Fe) for Chemotherapy–Ferroptosis Combined Therapy for Gastric Cancer

“…On the one hand, it is difficult to maintain a high concentration of chemotherapy drugs in the tumor site for a long time, leading to a decrease in the efficacy of chemotherapy and drug resistance in tumor cells. On the other hand, systemic administration may lead to severe side effects and adverse reactions, causing damage to healthy tissues and organs. − Therefore, it is of great research significance to develop new tumor treatment methods and skillfully combine them with traditional chemotherapy to overcome the limitations of traditional chemotherapy and improve its efficacy at the same time.…”