MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status

Ruth Louise Vinall, Alexandra Z. Ripoll, Sisi Wang, Chong-Xian Pan, Ralph W deVere White

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

MiR-34a is a downstream effector of p53 that has been shown to target several molecules associated with cell cycle and cell survival pathways. As alterations in these pathways are frequent in muscle invasive transitional cell carcinoma of the bladder (MI-TCC), for example mutation or loss of p53 and Rb, the goal of this study was to determine whether manipulation of miR-34a expression levels could abrogate the effect of these alterations and sensitize bladder cancer cells to chemotherapy. We demonstrate that transfection of T24, TCCSUP and 5637 with pre-miR-34a followed by cisplatin treatment results in a dramatic reduction in clonogenic potential and induction of senescence compared to treatment with cisplatin alone. Molecular analyses identified Cdk6 and sirtuin (SIRT)-1 as being targeted by miR-34a in MI-TCC cells, however, inhibition of Cdk6 and SIRT-1 was not as effective as pre-miR-34a in mediating chemosensitization. Analysis of 27 preneoadjuvant chemotherapy patient samples revealed many of the patients who subsequently did not respond to treatment (based on surgical resection postchemotherapy and 5-year survival data) express lower levels of miR-34a, however, a statistically significant difference between the responder and nonresponder groups was not observed (p = 0.1174). Analysis of eight sets of pre- and postneoadjuvant chemotherapy patient samples determined miR-34a expression increased postchemotherapy in only two of the eight patients. The combined data indicate that elevation of miR-34a expression levels before chemotherapy would be of benefit to MI-TCC patients, particularly in a setting of low miR-34a expression.

Original languageEnglish (US)
Pages (from-to)2526-2538
Number of pages13
JournalInternational Journal of Cancer
Volume130
Issue number11
DOIs
StatePublished - Jun 1 2012

Fingerprint

Urinary Bladder Neoplasms
Cisplatin
Transitional Cell Carcinoma
Sirtuin 1
Drug Therapy
Urinary Bladder
Muscles
Therapeutics
Transfection
Cell Survival
Cell Cycle
Mutation
Survival

Keywords

  • chemosensitivity
  • cisplatin
  • MiR-34a
  • muscle invasive bladder cancer
  • p53
  • Rb

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. / Vinall, Ruth Louise; Ripoll, Alexandra Z.; Wang, Sisi; Pan, Chong-Xian; deVere White, Ralph W.

In: International Journal of Cancer, Vol. 130, No. 11, 01.06.2012, p. 2526-2538.

Research output: Contribution to journalArticle

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