Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.

/pdf/noncoding-rnas-in-gastric-cancer-implications-for-drug-3w5e7wjv27.pdf

Noncoding RNAs in gastric cancer: implications for drug resistance

Methyltransferase-like 1 (METTL1) mediated 7-methylguanosine (m7G) is crucial for the regulation of chemoresistance in cancer treatment. However, the role of METTL1 in regulating chemoresistance of colon cancer (CC) cells to cisplatin is still unclear. This study established the cisplatin-resistant CC (CR-CC) cells and found that METTL1 was low-expressed in CR-CC cells compared to their paired cisplatin-sensitive CC (CS-CC) cells. Besides, overexpressed METTL1 enhanced the cytotoxic effects of cisplatin on CR-CC cells. In addition, miR-149-3p was the downstream target of METTL1, which could be positively regulated by METTL1. Further results validated that miR-149-3p was low-expressed in CR-CC cells comparing to the CS-CC cells. In addition, the promoting effects of overexpressed METTL1 on cisplatin induced CR-CC cell death were abrogated by synergistically knocking down miR-149-3p. Furthermore, S100A4/p53 axis was the downstream target of METTL1 and miR-149-3p, and either overexpressed METTL1 or miR-149-3p increased p53 protein levels in CR-CC cells, which were reversed by upregulating S100A4. Similarly, the promoting effects of overexpressed METTL1 on cisplatin-induced CR-CC cell death were abrogated by overexpressing S100A4. Taken together, overexpression of METTL1 sensitized CR-CC cells to cisplatin by modulating miR-149-3p/S100A4/p53 axis.

/pdf/overexpressed-methyltransferase-like-1-mettl1-increased-4ubk8obqzf.pdf

Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis.

Paclitaxel (PTX) is widely used as a front-line chemotherapy for breast cancer treatment. However, its clinical applications are limited by the development of chemoresistance. The objective of this study was to investigate the reversal effects of ursolic acid (UA) on PTX resistance and the possible mechanisms in breast cancer. The role of miRNA-149-5p/MyD88 in the regulation of PTX resistance was investigated by the transfection of breast cancer cells with MDA-MB-231 (231) and MDA-MB-231/PTX-resistance (231/PTX) with lentiviruses carrying the MyD88 gene, shRNA specific for MyD88, the miR-149-5p gene, and shRNA specific for miR-149-5p. The PTX sensitivity was assessed by a CCK-8 assay. qRT-PCR and Western blot analyses were used to detect changes in the mRNA and protein levels. Flow cytometry was used to measure the rate of cell apoptosis. A luciferase activity assay was used to detect the binding site of miR-149-5p on the 3'UTR of MyD88. 231/PTX cells were injected into the flanks of female athymic nude mice, and the mice were randomly divided into the five following groups: PBS, PTX (low), PTX (high), UA, and PTX+UA. Our data show that UA reversed the resistance of breast cancer 231/PTX cells to PTX in vitro and in vivo. UA treatment significantly increased the expression of miR-149-5p, which was lower in 231/PTX cells than in 231 cells. Furthermore, the overexpression of miR-149-5p increased the sensitivity of 231/PTX cells to PTX treatment, whereas the knockdown of the miR-149-5p gene attenuated the effects of UA on the regulation of PTX sensitivity. A luciferase assay demonstrated that miR-149-5p could directly regulate the transcriptional activity of MyD88, a known PTX-resistance gene, by targeting the 3'UTR of MyD88. Meanwhile, the downregulation of MyD88 through the overexpression of miR-149-5p or UA treatment inhibited the activation of the Akt signaling pathway in 231/PTX cells. Thus, our data indicate that UA can reverse PTX resistance by targeting the miRNA-149-5p/MyD88 axis in breast cancer cells.

/pdf/ursolic-acid-reverses-the-chemoresistance-of-breast-cancer-2d0cyo0o4a.pdf

Ursolic Acid Reverses the Chemoresistance of Breast Cancer Cells to Paclitaxel by Targeting MiRNA-149-5p/MyD88.

Background: Gastric cancer (GC) is one of the main mortality cause worldwide. Previously, we found Forkhead box protein (FOXM1) or Urokinase-type plasminogen activator (PLAU) are independent prognostic markers of GC. This study aims to explore the combining prognostic efficacy and the potential insights underlying additive effect of FOXM1 to PLAU in GC progression through in-silico analyses. Method: The expression of FOXM1 and PLAU were profiled in 33 cancer types using public data. A merged GC expression dataset containing 598 samples was used for evaluating prognostic significance of FOXM1/PLAU. Gene Set Enrichment Analysis (GSEA) was performed to elucidate the mechanisms underlying FOXM1/PLAU promoted GC progression. The Cancer Genome Atlas (TCGA) was used for analyzing the association between FOXM1/PLAU and tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were also computed using TCGA GC data. Drugs targeting FOXM1/PLAU associated gene expression pattern was analyzed using LINCs database. Results: FOXM1 and PLAU are overexpressed in 17/33 cancer types including GC. Kaplan-Meier analyses indicate that the FOXM1+PLAU+ subgroup have the worst prognosis, while FOXM1-PLAU- subgroup have the best survival. Bioinformatics analysis indicated that FOXM1+PLAU+ associated genes are enriched in TGF-beta, DNA repair and drug resistance signaling pathways; FOXM1 and PLAU expression are negatively correlated with tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were presented. Data mining from LINCs suggested several chemicals or drugs that could target the gene expression pattern of FOXM1+PLAU+ patients. Conclusion: FOXM1+PLAU+ can serve as effective prognostic biomarkers and potential therapeutic targets for GC. Due to the additive effect of these two genes, screening for drugs or chemicals that targeting the expression patterns PLAU+FOXM1+ subgroup may exert important clinical impact on GC management.

/pdf/foxm1-functions-collaboratively-with-plau-to-promote-gastric-3vexee7i24.pdf

FOXM1 functions collaboratively with PLAU to promote gastric cancer progression.

Cisplatin is an election drug widely used in clinic for the treatment of advanced gastric cancer. However, the heterogeneity of the gastric tumors and its resistance to the drugs, make in some cases the response very low and the prognosis unpredictable. In this manuscript we aim to find the molecular processes involved in cisplatin-induced apoptosis in two gastric cancer cell lines with different sensitivity to the treatment: AGS and MKN45. The apoptosis induction is higher in MKN45 than in AGS cells in response to CDDP. The intrinsic apoptotic pathway study revealed that MKN45 cells undergo degradation of Mcl-1 together with an increase of Bid and Bad levels, which results in sensitivity to CDDP. In addition, DNA repair NER pathway is impair in MKN45 cells due to low levels of XPC and the absence of translocation of XPA and XPD to the nucleus after stimuli. Altogether, these results suggest that NER and Bcl-2 protein family proteins are potential targets to improve the response to cisplatin treatment.

/pdf/xpa-xpc-and-xpd-modulate-sensitivity-in-gastric-cisplatin-4bbjjq3h48.pdf

XPA, XPC, and XPD Modulate Sensitivity in Gastric Cisplatin Resistance Cancer Cells.

Drug resistance remains a major unresolved obstacle for gastric cancer (GC) treatment. Recently, increasing studies have showen that microRNAs (miRNAs) are involved in cancer chemotherapeutic resistance and can potentially be applied to reverse drug resistance in cancers. The relationship between miRNA-149 expression and cisplatin (DDP) resistance in GC cells is still unknown. Here, we detected miR-149 expression by using RT-PCR and found that expression of miR-149 was downregulated in SGC7901/DDP cells compared with SGC7901cells, indicating a role of miR-149 in determining cisplatin-resistance of GC cells. Then, SGC7901/DDP cells were tansfected with miR-149 mimics, MTT assay was performed to determine SGC7901/DDP cell viability, and showed that overexpression of miR-149 inhibited the cell viability after cisplatin treatment, suggesting that up-regulation of miR-149 enhanced SGC7901/DDP cell sensitivity to cisplatin. Furthermore, we confirmed that Forkhead box M1 (FoxM1) is a direct target of miR-149 in SGC7901/DDP cells by using luciferase reporter assay. Besides, we also demonstrated that miR-149 enhances SGC7901/DDP cell sensitivity to cisplatin by downregulating FoxM1 expression. In summary, our data provide new insights that miR-149 plays an important role in determining sensitivity of cisplatin-resistant GC cells by targeting FoxM1 and suggest that miR-149 could be a potential target for reversing drug resistance in GC.

miR-149 reverses cisplatin resistance of gastric cancer SGC7901/DDP cells by targeting FoxM1.

Resistance to chemotherapy is a main obstacle for effective treatment of gastric cancer, the mechanism of which is still poorly understood. Forkhead box M1 (FoxM1) plays an important role in chemo-resistance of various tumors. This study aimed to explore whether FoxM1 mediated resistance of the gastric cancer cell line SGC7901 to the chemotherapy agent cisplatin (DDP). In the study, we detected FoxM1 and Mcl-1 expression via real time-PCR and western blot and demonstrated that FoxM1 is overexpressed in cisplatin-resistance GC cells and Mcl-1 expression is regulated by FoxM1. We examined SGC7901/DDP cell viability by MTT assay, which revealed that suppression of the FoxM1/Mcl-1 pathway impaired cell viability and thus increased sensitivity to cisplatin in gastric cancer cells. Taken together, the study implied that the FoxM1/Mcl-1 pathway may overcome cispaltin resistance of gastric cancer and provide a new therapeutic target for the treatment of gastric cancer.

Knockdown of the FoxM1 enhances the sensitivity of gastric cancer cells to cisplatin by targeting Mcl-1.

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miR-149 reverses cisplatin resistance of gastric cancer SGC7901/DDP cells by targeting FoxM1.

Knockdown of the FoxM1 enhances the sensitivity of gastric cancer cells to cisplatin by targeting Mcl-1.