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. 2020 Mar;43(3):965-974.
doi: 10.3892/or.2020.7471. Epub 2020 Jan 17.

"VSports最新版本" Downregulation of GPSM2 is associated with primary resistance to paclitaxel in breast cancer

Zhe Zhang #  1 , Zhi Li #  2 , Mingming Deng #  3 , Bofang Liu  4 , Xing Xin  5 , Zhenkun Zhao  1 , Ye Zhang  6 , Qingjie Lv  1
Affiliations

Downregulation of GPSM2 is associated with primary resistance to paclitaxel in breast cancer

Zhe Zhang et al. Oncol Rep. 2020 Mar.

Abstract

Paclitaxel is one of the most effective chemotherapy drugs for breast cancer worldwide but 20‑30% patients show primary resistance to the drug. Screening and identification of markers that facilitate effective and rapid prediction of sensitivity to paclitaxel is therefore an urgent medical requirement. In the present study, G protein signaling modulator 2 (GPSM2) mRNA levels were significantly associated with taxane sensitivity in experiments based on the Gene Expression Omnibus (GEO) online database. Immunohistochemical analysis consistently revealed a significant association of GPSM2 protein levels with paclitaxel sensitivity in breast cancer patients. Knockdown of GPSM2 reduced the sensitivity of breast cancer cells to paclitaxel via regulation of the cell cycle. Animal experiments further corroborated our in vitro findings. These results suggest that GPSM2 plays an important role in breast cancer resistance, supporting its utility as a potential target for improving drug susceptibility in patients as well as a marker of paclitaxel sensitivity. VSports手机版.

Keywords: breast cancer; GPSM2; paclitaxel; cell cycle V体育安卓版. .

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Figures

Figure 1.
Figure 1.
Online database screening for relevant genes closely related to paclitaxel primary drug resistance. (A) Venn plot showing 410 genes shared by the three GEO datasets. (B) Venn plot showing 5 genes shared by NSC125973 and NSC758645. (C) Significant gene sets with GPSM2 high-expression phenotypes when hallmarks were used as a reference. (D) Significant gene sets with GPSM2 high-expression phenotypes when KEGG signaling pathways were used as a reference. (E) Overlapping gene sets from the two above GSEA analyses. KEGG, Kyoto Encyclopedia of Genes and Genomes; OBFC1, oligonucleotide/oligosaccharide-binding fold containing 1; SREK1IP1, splicing regulatory glutamine/lysine-rich protein 1 interacting protein 1; RCC4, regulator of chromosome condensation 1; GPSM2, G protein signaling modulator 2; WBP1L, WW domain binding protein 1 like.
Figure 2.
Figure 2.
High GPSM2 protein expression is valuable to predict resistance to PTX in breast cancer patients. (A) Representative images of GPSM2 staining in human breast tissue samples: ‘−’ (negative staining intensity), ‘+’ (weak staining intensity), ‘++’ (moderate staining intensity), and ‘+++’ (strong staining intensity) (Scale bar, 300 µm). (B) IHC scores of GPSM2 were significantly reduced in PTX-resistant tissues relative to PTX-sensitive tissues (*P<0.05). (C) IHC scores of GPSM2 were significantly reduced in patients with lymph node-negative status, compared to those with lymph node-positive status (***P<0.05). PTX, paclitaxel; GPSM2, G protein signaling modulator 2; IHC, immunohistochemistry.
Figure 3.
Figure 3.
Knockdown of GPSM2 increases resistance to PTX in breast cancer MDA-MB-231 cells. (A and B) GPSM2 mRNA and protein expression in three breast cancer cell lines (T47D, MCF7 and MDA-MB-231). (C) Cell proliferation assays were performed following treatment with different concentrations (0, 0.1, 0.5, 1, 5 and 10 µg/ml) of PTX in the three breast cancer cell lines. (D and E) MDA-MB-231 cells were transfected with either GPSM2-siRNA or NC-siRNA and GPSM2 mRNA and protein expression levels were detected via RT-qPCR and western blot analyses, respectively. **P<0.01 vs. the NC group. (F) Cell viability assay showing that GPSM2 knockdown increased the resistance of MDA-MB-231 cells to PTX. *P<0.05. (G) After treatment with PTX, the number of colonies formed by MDA-MB-231 cells transfected with NC siRNA was lower than those formed by cells transfected with GPSM2 siRNA. *P<0.05; ns, not significant. (H) MDA-MB-231 cells were transfected with either GPSM2-WT or empty vector plasmid and GPSM2 protein expression was detected via western blot analyses. (I) Cell viability assay showing that GPSM2 overexpression decreased the resistance of MDA-MB-231 cells to PTX. *P<0.05. (J) After treatment with PTX, the number of colonies formed by MDA-MB-231 cells transfected with the empty vector plasmid was higher than the number formed by cells transfected with the GPSM2-WT plasmid. *P<0.05; ns, not significant. (K) GPSM2 affects the activity of PTX to trigger G2 phase arrest in breast cancer. GPSM2 knockdown reduced paclitaxel-induced G2 phase arrest. *P<0.05. PTX, paclitaxel; GPSM2, G protein signaling modulator 2; NC, negative control.
Figure 4.
Figure 4.
Combination treatment with GPSM2 shRNA and PTX in a nude mouse model. (A) Representative images of tumors isolated from each group after inoculation of MDA-MB-231 cells exposed to the different treatments (NC, shRNA, NC+PTX and shRNA+PTX). (B) Tumor volumes in orthotopic implantation model mice. (C) Weights of tumors in orthotopic implantation model mice. *P<0.05. PTX, paclitaxel; GPSM2, G protein signaling modulator 2; NC, negative control.
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