Rab23 promotes the cisplatin resistance of ovarian cancer via the Shh-Gli-ABCG2 signaling pathway

Zhang,Wenjie; Yu,Feng; Wang,Yu; Zhang,Yu; Meng,Lingxin; Chi,Yuhua

doi:10.3892/ol.2018.7949

Rab23 promotes the cisplatin resistance of ovarian cancer via the Shh-Gli-ABCG2 signaling pathway

Authors:
- Wenjie Zhang
- Feng Yu
- Yu Wang
- Yu Zhang
- Lingxin Meng
- Yuhua Chi
View Affiliations

Affiliations: Oncology Department, Rizhao People's Hospital, Rizhao, Shandong 276800, P.R. China, Gynaecology Department, Maternal and Child Health Care and Family Planning Service Center of Rizhao City, Rizhao, Shandong 276826, P.R. China, Emergency Internal Medicine Department, Central Hospital of Rizhao City, Rizhao, Shandong 276800, P.R. China, Blood Drawing Department, Central Blood Station of Rizhao City, Rizhao, Shandong 276800, P.R. China
Published online on: February 5, 2018 https://doi.org/10.3892/ol.2018.7949
Pages: 5155-5160

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

As a novel member of the Rab GTPase family, the role of Rab23 has been reported in multiple types of tumor. However, to the best of our knowledge, the role of Rab23 in ovarian cancer (OC) has not yet been reported. In the present study, immunohistochemistry analysis demonstrated that Rab23 was upregulated in OC tissue; survival analysis indicated that Rab23 expression was associated with a reduced overall survival (OS) rate and disease‑free survival (DFS) time. In vitro experiments also demonstrated the increased expression of Rab23 in the OC cells lines, A2780 and SKOV‑3, compared with in the normal ovarian cell line, IOSE80. Following the silencing of ABCG2 in SKOV‑3 cells, ATP‑binding cassette sub‑family G member 2 (ABCG2) expression was significantly downregulated both at the RNA and protein levels. The cisplatin (DDP) IC50 declined from 43.09±7.12 µmol/l in control cells to 26.46±5.38 µmol/l in SKOV‑3 cells with silenced Rab23. In contrast, in A2780 cells overexpressing Rab23 (A2780‑Rab23), ABCG2 expression was significantly upregulated and the DDP IC50 increased from 27.42±6.54 µmol/l in control cells to 45.92±5.23 µmol/l in A2780‑Rab23. Investigation into the potential molecular mechanisms for this revealed that the expression of sonic hedgehog (Shh) and Gli family zinc finger 1 (Gli1) was increased in A2780‑Rab23 cells, whereas silencing Rab23 in SKOV‑3 cells significantly inhibited the expression of Shh and Gli1. The Gli1 inhibitor GANT‑61 significantly abrogated the increased ABCG2 expression in A2780‑Rab23 cells. Furthermore, the DDP IC50 in A2780‑Rab23 cells decreased significantly following the silencing of ABCG2 expression; the IC50 declined from 51.66±8.32 µmol/l in A2780‑Rab23 cells to 25.61±6.17 µmol/l in A2780‑Rab23 cells with silenced ABCG2. Collectively, the results indicate that Rab23 promotes the DDP resistance of OC cells via the Shh‑Gli1‑ABCG2 pathway, providing the proof of principle for the further investigation of drug resistance therapy targeting Rab23.

View Figures

View References

1	Huo J, Bian XH, Huang Y, Miao ZC and Song LH: Inhibitory effect and mechanism of metformin on human ovarian cancer cells SKOV-3 and A2780. Eur Rev Med Pharmacol Sci. 21:484–489. 2017.PubMed/NCBI
2	Li R, Dong T, Hu C, Lu J, Dai J and Liu P: Salinomycin repressed the epithelial-mesenchymal transition of epithelial ovarian cancer cells via downregulating Wnt/b-catenin pathway. Onco Targets Ther. 10:1317–1325. 2017. View Article : Google Scholar : PubMed/NCBI
3	Perroud HA, Scharovsky OG, Rozados VR and Alasino CM: Clinical response in patients with ovarian cancer treated with metronomic chemotherapy. Ecancermedicalscience. 11:7232017. View Article : Google Scholar : PubMed/NCBI
4	Lee HH, Bellat V and Law B: Chemotherapy induces adaptive drug resistance and metastatic potentials via phenotypic CXCR4-expressing cell state transition in ovarian cancer. PLoS One. 12:e01710442017. View Article : Google Scholar : PubMed/NCBI
5	Chen Y, Ng F and Tang BL: Rab23 activities and human cancer-emerging connections and mechanisms. Tumour Biol. 37:12959–12967. 2016. View Article : Google Scholar : PubMed/NCBI
6	Jian Q, Miao Y, Tang L, Huang M, Yang Y, Ba W, Liu Y, Chi S and Li C: Rab23 promotes squamous cell carcinoma cell migration and invasion via integrin b1/Rac1 pathway. Oncotarget. 7:5342–5352. 2016. View Article : Google Scholar : PubMed/NCBI
7	Wang M, Dong Q and Wang Y: Rab23 is overexpressed in human astrocytoma and promotes cell migration and invasion through regulation of Rac1. Tumour Biol. 37:11049–11055. 2016. View Article : Google Scholar : PubMed/NCBI
8	Denning KM, Smyth PC, Cahill SF, Finn SP, Conlon E, Li J, Flavin RJ, Aherne ST, Guenther SM, Ferlinz A, et al: A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples. Mod Pathol. 20:1095–1102. 2007. View Article : Google Scholar : PubMed/NCBI
9	Liu Y, Zeng C, Bao N, Zhao J, Hu Y, Li C and Chi S: Effect of Rab23 on the proliferation and apoptosis in breast cancer. Oncol Rep. 34:1835–1844. 2015. View Article : Google Scholar : PubMed/NCBI
10	Cai ZZ, Xu LB, Cai JL, Wang JS, Zhou B and Hu H: Inactivation of Rab23 inhibits the invasion and motility of pancreatic duct adenocarcinoma. Genet Mol Res. 14:2707–2715. 2015. View Article : Google Scholar : PubMed/NCBI
11	Chang J, Xu W, Liu G, Du X and Li X: Downregulation of Rab23 in prostate cancer inhibits tumor growth in vitro and in vivo. Oncol Res. 25:241–248. 2017. View Article : Google Scholar : PubMed/NCBI
12	Nishihashi K, Kawashima K, Nomura T, Urakami-Takebayashi Y, Miyazaki M, Takano M and Nagai J: Cobalt chloride induces expression and function of breast cancer resistance protein (BCRP/ABCG2) in human renal proximal tubular epithelial cell line HK-2. Biol Pharm Bull. 40:82–87. 2017. View Article : Google Scholar : PubMed/NCBI
13	Wang J, Yunyun Z, Wang L, Chen X and Zhu Z: ABCG2 confers promotion in gastric cancer through modulating downstream CRKL in vitro combining with biostatistics mining. Oncotarget. 8:5256–5267. 2017.PubMed/NCBI
14	Kuo WY, Hwu L, Wu CY, Lee JS, Chang CW and Liu RS: STAT3/NF-kB-regulated lentiviral TK/GCV suicide gene therapy for cisplatin-resistant triple-negative breast cancer. Theranostics. 7:647–663. 2017. View Article : Google Scholar : PubMed/NCBI
15	Maeda O, Matsuoka A, Miyahara R, Funasaka K, Hirooka Y, Fukaya M, Nagino M, Kodera Y, Goto H and Ando Y: Modified docetaxel, cisplatin and capecitabine for stage IV gastric cancer in Japanese patients: A feasibility study. World J Gastroenterol. 23:1090–1097. 2017. View Article : Google Scholar : PubMed/NCBI
16	Xie XQ, Zhao QH, Wang H and Gu KS: Dysregulation of mRNA profile in cisplatin-resistant gastric cancer cell line SGC7901. World J Gastroenterol. 23:1189–1202. 2017. View Article : Google Scholar : PubMed/NCBI
17	Du Z, Zhou F, Jia Z, Zheng B, Han S, Cheng J, Zhu G and Huang P: The hedgehog/Gli-1 signaling pathways is involved in the inhibitory effect of resveratrol on human colorectal cancer HCT116 cells. Iran J Basic Med Sci. 19:1171–1176. 2016.PubMed/NCBI
18	Merchant JL and Ding L: Hedgehog signaling links chronic inflammation to gastric cancer precursor lesions. Cell Mol Gastroenterol Hepatol. 3:201–210. 2017. View Article : Google Scholar : PubMed/NCBI
19	Lee HJ, Wu Q, Li H, Bae GU, Kim AK and Ryu JH: A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells. Oncol Lett. 12:2912–2917. 2016. View Article : Google Scholar : PubMed/NCBI
20	Khatra H, Kundu J, Khan PP, Duttagupta I, Pattanayak S and Sinha S: Piperazic acid derivatives inhibit Gli1 in Hedgehog signaling pathway. Bioorg Med Chem Lett. 26:4423–4426. 2016. View Article : Google Scholar : PubMed/NCBI
21	Chi S, Xie G, Liu H, Chen K, Zhang X, Li C and Xie J: Rab23 negatively regulates Gli1 transcriptional factor in a Su(Fu)-dependent manner. Cell Signal. 24:1222–1228. 2012. View Article : Google Scholar : PubMed/NCBI
22	Fuller K, O'Connell JT, Gordon J, Mauti O and Eggenschwiler J: Rab23 regulates Nodal signaling in vertebrate left-right patterning independently of the Hedgehog pathway. Dev Biol. 391:182–195. 2014. View Article : Google Scholar : PubMed/NCBI