Prediction of key genes and pathways involved in trastuzumab-resistant gastric cancer

Yu, Chaoran; Xue, Peng; Pan, Ruijun; Cai, Zhenhao; He, Zengyou; Sun, Jing

doi:10.1186/s12957-018-1475-6

Cited by 24 publications

(24 citation statements)

References 69 publications

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“…Earlier research proved that the transcription factor EGR1 directly regulates the expression of miR148a-3p by binding to its promoter [31]. EGR1 is induced by treatment with anti-HER2 targeted therapies [32], including trastuzumab, and its expression is associated with favorable outcome in HER2 positive cancer models [33]. These evidence aided in better interpretation of our findings.…”

Section: Discussionsupporting

confidence: 72%

Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy

Cosimo

Appierto

Pizzamiglio

et al. 2020

IJMS

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Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) (p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%–68%), and 44% (95%CI 22%–69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23–9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%–81%) and 0% (95%CI 0%–31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.

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Section: Discussionsupporting

confidence: 72%

Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy

Cosimo

Appierto

Pizzamiglio

et al. 2020

IJMS

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“…We identified these two key pathways using the KEGG over-representation test based on the co-expressed genes of COL1A1 and GSEA, suggesting that COL1A1 promoted carboplatin resistance in OV through these pathways. According to previous studies, the “ECM-receptor interaction” pathway is involved in platinum- ( 38 ), paclitaxel-, and topotecan-resistant OV ( 39 ), trastuzumab-resistant gastric cancer ( 40 ), and temozolomide-resistant glioblastoma ( 41 ). Moreover, to date, many drug resistance mechanisms involving the extracellular matrix have been identified across cancer types; these mechanisms have been classified into a range of categories including physical barriers to treatment (hypoxia, pH, and interstitial fluid pressure) and cell-adhesion-associated drug resistance ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Detailed Molecular Mechanism and Potential Drugs for COL1A1 in Carboplatin-Resistant Ovarian Cancer

et al. 2021

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Carboplatin resistance in ovarian cancer (OV) is a major medical problem. Thus, there is an urgent need to find novel therapeutic targets to improve the prognosis of patients with carboplatin-resistant OV. Accumulating evidence indicates that the gene COL1A1 (collagen type I alpha 1 chain) has an important role in chemoresistance and could be a therapeutic target. However, there have been no reports about the role of COL1A1 in carboplatin-resistant OV. This study aimed to establish the detailed molecular mechanism of COL1A1 and predict potential drugs for its treatment. We found that COL1A1 had a pivotal role in carboplatin resistance in OV by weighted gene correlation network analysis and survival analysis. Moreover, we constructed a competing endogenous RNA network (LINC00052/SMCR5-miR-98-COL1A1) based on multi-omics data and experiments to explore the upstream regulatory mechanisms of COL1A1. Two key pathways involving COL1A1 in carboplatin resistance were identified by co-expression analysis and pathway enrichment: the “ECM-receptor interaction” and “focal adhesion” Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, combining these results with those of cell viability assays, we proposed that ZINC000085537017 and quercetin were potential drugs for COL1A1 based on virtual screening and the TCMSP database, respectively. These results might help to improve the outcome of OV in the future.

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“…As a common characteristic, OAS has been described as part of the type I IFN signaling, exerting a significant immunoregulatory role. Besides being involved in the progression of several diseases, OAS proteins have also been shown to contribute with resistance to the only approved treatment for gastric cancer [25] and oncolytic virus therapies for pancreatic ductal adenocarcinoma (PDA) [26].…”

Section: Introductionmentioning

confidence: 99%

In silicoidentification of potential inhibitors against human 2’-5’-oligoadenylate synthetase (OAS) proteins

Gonzalez

Giraldo

Gutiérrez

2019

Preprint

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As part of the type I IFN signaling, the 2’-5’- oligoadenylate synthetase (OAS) proteins have been involved in the progression of several non-viral diseases. Notably, OAS has been correlated with immune-modulatory functions that promote chronic inflammatory conditions, autoimmune disorders, cancer, and infectious diseases. In spite of this, OAS enzymes have been ignored as drug targets, and to date, there are no reports of compounds that can inhibit their activity. In this study, we have used homology modeling and virtual high-throughput screening to identify potential inhibitors of the human proteins OAS1, OAS2, and OAS3. Altogether, we have found 37 molecules that could exert a competitive inhibition in the ATP binding sites of OAS proteins, independently of the activation state of the enzyme. This latter characteristic, which might be crucial for a versatile inhibitor, was observed in compounds interacting with the residues Asp75, Asp77, Gln229, and Tyr230 in OAS1, and their equivalents in OAS2 and OAS3. Although there was little correlation between specific chemical fragments and particular interactions, intermolecular contacts with OAS catalytic triad and other critical amino acids were mainly promoted by heterocycles with π electrons and hydrogen bond acceptors. In conclusion, this study provides a potential set of OAS inhibitors as well as valuable information for their design, development, and optimization.

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Prediction of key genes and pathways involved in trastuzumab-resistant gastric cancer

Cited by 24 publications

References 69 publications

Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy

Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy

Detailed Molecular Mechanism and Potential Drugs for COL1A1 in Carboplatin-Resistant Ovarian Cancer

In silicoidentification of potential inhibitors against human 2’-5’-oligoadenylate synthetase (OAS) proteins

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