Dataset Information

Downregulation of HIPK2 increases resistance of bladder cancer cell to cisplatin by regulating Wip1.

ABSTRACT:

Unlabelled

Cisplatin-based combination chemotherapy regimen is a reasonable alternative to cystectomy in advanced/metastatic bladder cancer, but acquisition of cisplatin resistance is common in patients with bladder cancer. Previous studies showed that loss of homeodomain-interacting protein kinase-2 (HIPK2) contributes to cell proliferation and tumorigenesis. However, the role of HIPK2 in regulating chemoresistance of cancer cell is not fully understood. In the present study, we found that HIPK2 mRNA and protein levels are significantly decreased in cisplatin-resistant bladder cancer cell in vivo and in vitro. Downregulation of HIPK2 increases the cell viability in a dose- and time-dependent manner during cisplatin treatment, whereas overexpression of HIPK2 reduces the cell viability. HIPK2 overexpression partially overcomes cisplatin resistance in RT4-CisR cell. Furthermore, we showed that Wip1 (wild-type p53-induced phosphatase 1) expression is upregulated in RT4-CisR cell compared with RT4 cell, and HIPK2 negatively regulates Wip1 expression in bladder cancer cell. HIPK2 and Wip1 expression is also negatively correlated after cisplatin-based combination chemotherapy in vivo. Finally, we demonstrated that overexpression of HIPK2 sensitizes chemoresistant bladder cancer cell to cisplatin by regulating Wip1 expression.

Conclusions

These data suggest that HIPK2/Wip1 signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of bladder cancer.

SUBMITTER: Lin J

PROVIDER: S-EPMC4028303 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Downregulation of HIPK2 increases resistance of bladder cancer cell to cisplatin by regulating Wip1.

Lin Jun J Zhang Qiang Q Lu Yi Y Xue Wenrui W Xu Yue Y Zhu Yichen Y Hu Xiaopeng X

PloS one 20140520 5

<h4>Unlabelled</h4>Cisplatin-based combination chemotherapy regimen is a reasonable alternative to cystectomy in advanced/metastatic bladder cancer, but acquisition of cisplatin resistance is common in patients with bladder cancer. Previous studies showed that loss of homeodomain-interacting protein kinase-2 (HIPK2) contributes to cell proliferation and tumorigenesis. However, the role of HIPK2 in regulating chemoresistance of cancer cell is not fully understood. In the present study, we found t ...[more]

PMID: 24846322

Similar Datasets

Project description:BackgroundAccumulating evidence has revealed that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. Emerging evidence has demonstrated that miR-133a participates in the tumorigenesis of various cancers. However, whether miR-133a is associated with cisplatin resistance in ovarian cancer remains unclear.ObjectiveTo investigate the role of miR-133a in the development of cisplatin resistance in ovarian cancer.MethodsMiR-133a expression in cisplatin-resistant ovarian cancer cell lines was assessed by reverse-transcription quantitative PCR (RT-qPCR). A cell counting kit-8 (CCK-8) assay was used to evaluate the viability of tumour cells treated with cisplatin in the presence or absence of miR-133a. A luciferase reporter assay was used to analyse the binding of miR-133a with the 3' untranslated region (3'UTR) of YES proto-oncogene 1 (YES1). The YES1 expression level was analysed using a dataset from the International Cancer Genome Consortium (ICGC) and assessed by RT-qPCR and western blotting in vitro. The roles and mechanisms of YES1 in cell functions were further probed via gain- and loss-of-function analysis.ResultsThe expression of miR-133a was significantly decreased in cisplatin-resistant ovarian cancer cell lines (A2780-DDP and SKOV3-DDP), and the overexpression of the miR-133a mimic reduced cisplatin resistance in A2780-DDP and SKOV3-DDP cells. Treatment with the miR-133a inhibitor increased cisplatin sensitivity in normal A2780 and SKOV3 cells. MiR-133a binds the 3'UTR of YES1 and downregulates its expression. Bioinformatics analysis revealed that YES1 expression was upregulated in recurrent cisplatin-resistant ovarian cancer tissue, and in vitro experiments also verified its upregulation in cisplatin-resistant cell lines. Furthermore, we discovered that miR-133a downregulated the expression of YES1 and thus inhibited cell autophagy to reduce cisplatin resistance. Yes1 knockdown significantly suppressed the cisplatin resistance of ovarian cancer cells by inhibiting autophagy in vitro. Xenograft tumour implantation further demonstrated that Yes1 overexpression promoted ovarian tumour development and cisplatin resistance.ConclusionsOur results suggest that the miR-133a/YES1 axis plays a critical role in cisplatin resistance in human ovarian cancer by regulating cell autophagy, which might serve as a promising therapeutic target for ovarian cancer chemotherapy treatment in the future.

Dataset Information

Downregulation of HIPK2 increases resistance of bladder cancer cell to cisplatin by regulating Wip1.

Unlabelled

Conclusions

Publications

Downregulation of HIPK2 increases resistance of bladder cancer cell to cisplatin by regulating Wip1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets