1. Academic Validation
  2. miR-34a Regulates Multidrug Resistance via Positively Modulating OAZ2 Signaling in Colon Cancer Cells

miR-34a Regulates Multidrug Resistance via Positively Modulating OAZ2 Signaling in Colon Cancer Cells

  • J Immunol Res. 2018 Aug 2;2018:7498514. doi: 10.1155/2018/7498514.
Yong Li 1 Ping Gong 2 Ji-Xue Hou 3 Wei Huang 2 Xiao-Ping Ma 2 Yu-Li Wang 2 Jing Li 2 Xiao-Bin Cui 4 Na Li 2 5
Affiliations

Affiliations

  • 1 Department of Radiology, Suining Central Hospital, Suining, Sichuan Province 629000, China.
  • 2 Department of Medical Oncology, First Affiliated Hospital of Medical College of Shihezi University, Shihezi, Xinjiang Uygur Autonomous Region 832000, China.
  • 3 Department of General Surgery, 2nd Division, First Affiliated Hospital of Medical College of Shihezi University, Shihezi, Xinjiang Uygur Autonomous Region 832000, China.
  • 4 Department of Pathology, First Affiliated Hospital of Medical College of Shihezi University, Shihezi, Xinjiang Uygur Autonomous Region 832000, China.
  • 5 Cancer Center of Suining Central Hospital, Suining, Sichuan Province 629000, China.
Abstract

Although aberrant expression of miR-34a, an essential tumor suppressor miRNA, has been frequently observed in colon Cancer (CCa), whether miR-34a can regulate CCa progression by modulating other facets of this malignancy (such as multidrug resistance, MDR) remains unknown. Here, we report for the first time that miR-34a expression was significantly downregulated in clinical CCa samples from oxaliplatin-resistant patients and in experimentally established multidrug-resistant CCa cells. By using histoculture drug response assay, we further confirmed that clinical CCa samples with lower miR-34a expression appeared to be more resistant to chemotherapy. Functionally, ectopic expression of exogenous miR-34a resensitized multidrug-resistant HCT-8/OR cells to oxaliplatin treatment, whereas miR-34a inhibition augmented the oxaliplatin resistance in chemosensitive HCT-8 cells. Mechanistically, miR-34a positively regulated the mRNA stability of the ornithine decarboxylase antizyme 2 (OAZ2) by directly targeting its three prime untranslated region (3'UTR). Consequently, suppression of the expression of miR-34a/OAZ2 signaling by chemotherapeutic agents significantly enhanced the activation of MDR-associated ATP-binding cassette (ABC) transporters and antiapoptosis pathways, thus leading to MDR development in CCa cells. Collectively, our combined analysis reveals a critical role of miR-34a/OAZ2 cascade in conferring a proper cellular response to CCa chemotherapy.

Figures
Products