Abstract

Background: Gastric cancer (GC) is a public health problem worldwide. Many signaling pathways chemical inhibitors have been developed to complement routine chemotherapy, usually based on cisplatin (CDDP) and/or 5-fluorouracil (5-FU). However, both chemical inhibitors and chemotherapeutics have shown resistance features in cancer patients. Therefore, it is pivotal to characterize new molecules that could improve treatment outcomes and offer broader options for patients. Long non-coding RNAs (lncRNAs)- epigenetic regulators that could lead to drug resistance- have recently emerged for this purpose. Methods: 19 treatment-naïve GC tissues (11 responders to CDDP/5-FU, and 8 nonresponders to CDDP/5-FU), and 6 GC cell lines: wild-type (WT) AGS and MKN28; CDDP-resistant AGS and MKN28; and 5-FU-resistant AGS and MKN28 cells were sequenced by RNA-seq to determine the differentially expressed protein-coding genes (DEGs) and lncRNAs. Gene ontology, functional enrichment and prediction analyses were performed by several in silico tools. Results: About 570 DEGs were differentially expressed (280 upregulated, 290 repressed), evidencing enrichment of “translation functions” and “anabolic functions”, implicating the PI3K/AKT/mTOR pathway. Glimma-plots showed that GC cases non-responders to CDDP/5-FU and/or resistant cell lines had a higher expression of AKT1, MTOR, RPS6KB1 genes, and especially PIK3CA gene compared to controls (p<0.005). Conversely, PTEN was repressed in these cases. Moreover, 57 lncRNAs were differentially expressed in non-responder GC tissues and resistant cell lines (34 upregulated, 23 repressed). 3 of the upregulated lncRNAs (AP000350.5, AC0022007.1, and FAM2254) showed a strong interaction with PIK3CA, AKT1, MTOR and RPS6KB1 genes, potentially acting as gene enhancers or competing-endogenous RNAs. Conclusions: This study suggests that the upregulation of these 3 lncRNAs causes activation of the PI3K/AKT/mTOR pathway, which leads to chemoresistance to CDDP and/or 5-FU. Therefore, the biological or chemical repression of these lncRNAs could reduce this pathway activation, inducing re-sensitization of CDDP/5-FU-resistant GC tumors. Legal entity responsible for the study: Ismael Riquelme. Funding: DIUAV 03-2022; FONDECYT 11240398. Disclosure: All authors have declared no conflicts of interest.