Abstract
BackgroundChemoresistance is a main obstacle in gastric cancer (GC) treatment, but its molecular mechanism still needs to be elucidated. Here, we aim to reveal the underlying mechanisms of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resistance in GC.MethodsWe performed RNA sequencing (RNA-seq) on samples from patients who were resistant or sensitive to nab-paclitaxel, and identified Zinc Finger Protein 64 (ZFP64) as critical for nab-paclitaxel resistance in GC. CCK8, flow cytometry, TUNEL staining, sphere formation assays were performed to investigate the effects of ZFP64 in vitro, while subcutaneous tumor formation models were established in nude mice or humanized mice to evaluate the biological roles of ZFP64 in vivo. Chromatin immunoprecipitation sequencing (CHIP-seq) and double-luciferase reporter gene assay were conducted to reveal the underlying mechanism of ZFP64.ResultsZFP64 overexpression was linked with aggressive phenotypes, nab-paclitaxel resistance and served as an independent prognostic factor in GC. As a transcription factor, ZFP64 directly binds to Galectin-1 (GAL-1) promoter and promoted GAL-1 transcription, thus inducing stem-cell like phenotypes and immunosuppressive microenvironment in GC. Importantly, compared to treatment with nab-paclitaxel alone, nab-paclitaxel plus GAL-1 blockade significantly enhanced the anti-tumor effect in mouse models, particularly in humanized mice.ConclusionsOur data support a pivotal role for ZFP64 in GC progression by simultaneously promoting cellular chemotherapy resistance and tumor immunosuppression. Treatment with the combination of nab-paclitaxel and a GAL-1 inhibitor might benefit a subgroup of GC patients.
Highlights
Chemoresistance is a main obstacle in gastric cancer (GC) treatment, but its molecular mechanism still needs to be elucidated
Zinc Finger Protein 64 (ZFP64) exhibits upregulated expression in nab‐paclitaxel resistant GC To screen the key genes resulting to nab-Paclitaxel resistance in GC, four paired samples from patients who were resistant or sensitive to AS-based neoadjuvant chemotherapy were collected for RNA sequencing (RNA-seq) analysis
Some previously reported chemoresistance-related genes, such as P glycoprotein (P-gp), adenosine triphosphate-binding cassette superfamily G member 2 (ABCG2), and multidrug resistant associate protein (MRP) were not found in our analysis results, indicating a novel mechanism might be involved in chemotherapy resistance of GC
Summary
Chemoresistance is a main obstacle in gastric cancer (GC) treatment, but its molecular mechanism still needs to be elucidated. The underlaying mechanism of nab-paclitaxel resistance in GC remains ambiguous and needs a deeper understanding at the molecular level to benefit a subset of patients with GC. Accumulating experimental evidence has revealed that targeting markers of CSCs, related pathways or microenvironmental niches might impair chemoresistance [8, 9]. Despite these debates about the CSC origin, stemness maintenance and continuous differentiation, an urgent and continuous need is to improve our understanding of the function and behavior of CSCs in cancer progression and chemoresistance
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