miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer.
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.
Liu
W
W
Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA. liuwei3@mail.nih.gov
Zabirnyk
O
O
Wang
H
H
Shiao
Y-H
YH
Nickerson
M L
ML
Khalil
S
S
Anderson
L M
LM
Perantoni
A O
AO
Phang
J M
JM
D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D011394:Proline Oxidase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D011394:Proline Oxidase