miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer

• Published in: Oncogene Vol. 29; no. 35; pp. 4914 - 4924
• Main Authors: Liu, W, Zabirnyk, O, Wang, H, Shiao, Y-H, Nickerson, M L, Khalil, S, Anderson, L M, Perantoni, A O, Phang, J M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2010; Nature Publishing Group
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; 631/337/384/331; 631/67/581; 692/699/67/395; 692/699/67/589/1588; Active oxygen; Apoptosis; Base Sequence; Biological and medical sciences; Cancer; Carcinoma, Renal cell; Cell Biology; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Down-Regulation - genetics; Epigenetics; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Genetic diversity; Human Genetics; Humans; Hypoxia-inducible factors; Internal Medicine; Kidney cancer; Kidney diseases; Kidney Neoplasms - enzymology; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Medical sciences; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs - genetics; Mitochondria; Molecular and cellular biology; mRNA; Nephrology. Urinary tract diseases; Oncology; original-article; Physiological aspects; Proline oxidase; Proline Oxidase - genetics; Proline Oxidase - metabolism; Proteins; Reactive oxygen species; Renal cell carcinoma; Risk factors; RNA, Messenger - genetics; Signal transduction; Tumor suppressor genes; Tumor suppressor proteins; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Tumors of the urinary system; United States; renal cancer; tumor suppressor; proline oxidase; miR-23b; ROS; Kidney disease; Urinary system disease; RNA interference; Enzyme; Micro RNA; Oxidase; Proline; Malignant tumor; Carcinogenesis; Protein; Gene silencing; Kidney cancer; Oxidoreductases; Cancer; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.237

Proline oxidase (POX) is a novel mitochondrial tumor suppressor that can suppress proliferation and induce apoptosis through the generation of reactive oxygen species (ROS) and decreasing hypoxia-inducible factor (HIF) signaling. Recent studies have shown the absence of expression of POX in human cancer tissues, including renal cancer. However, the mechanism for the loss of POX remains obscure. No genetic or epigenetic variation of POX gene was found. In this study, we identified the upregulated miR-23b* in renal cancer as an important regulator of POX. Ectopic overexpression of miR-23b* in normal renal cells resulted in striking downregulation of POX, whereas POX expression increased markedly when endogenous miR-23b* was knocked down by its antagomirs in renal cancer cells. Consistent with the POX-mediated tumor suppression pathway, these antagomirs induced ROS, inhibited HIF signaling and increased apoptosis. Furthermore, we confirmed the regulation of miR-23b* on POX and its function in the DLD1 Tet-off POX cell system. Using a luciferase reporter system, we verified the direct binding of miR-23b* to the POX mRNA 3′-untranslated region. In addition, pairs of human renal carcinoma and normal tissues showed a negative correlation between miR-23b* and POX protein expression, providing its clinical corroboration. Taken together, our results suggested that miR-23b*, by targeting POX, could function as an oncogene; decreasing miR-23b* expression may prove to be an effective way of inhibiting kidney tumor growth.