Association of microRNA-34a overexpression with proliferation is cell type-dependent.
Recently Welch et al. reported that microRNA (miRNA)-34a functions as a potential tumor suppressor in neuroblastoma cells (Oncogene 26: 5017-22, 2007). Here, we conversely show that miRNA-34a supports cell proliferation in rat oxidative stress-induced renal carcinogenesis and is overexpressed in various types of human cancers. While searching for genetically unstable chromosomal areas in rat renal carcinogenesis, we found the miRNA-34 family reciprocally overexpressed in chromosomal areas with frequent allelic loss. By in situ hybridization and reverse transcription-polymerase chain reaction, cerebral neurons and Purkinje cells showed the highest expression of a major type, miRNA-34a, followed by a variety of endocrine cells and proliferating cells including germinal center lymphocytes and mouse embryonic fibroblasts and stem cells. In contrast, normal renal tubules, hepatocytes and myocardial cells showed faint expression. After 3 weeks of ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress, regenerating renal proximal tubular cells showed high miRNA-34a expression. All of the Fe-NTA-induced rat renal carcinomas and an array of human cancers (151 positive cases of 177) showed high expression of miRNA-34a. Furthermore, knockdown of miRNA-34a with small interfering RNA significantly suppressed proliferation not only of renal carcinoma cells but also of HeLa and MCF7 cells. These results indicate that miRNA-34a overexpression, an acquired trait during carcinogenesis, supports cell proliferation in the majority of cancers suggesting an unexpected link in the cellular metabolism between cancer and neuronal and/or endocrine cells, which warrants further investigation.
Dutta
Khokon Kumar
KK
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Zhong
Yi
Y
Liu
Yu-Ting
YT
Yamada
Takuji
T
Akatsuka
Shinya
S
Hu
Qian
Q
Yoshihara
Minako
M
Ohara
Hiroki
H
Takehashi
Masanori
M
Shinohara
Takashi
T
Masutani
Hiroshi
H
Onuki
Janice
J
Toyokuni
Shinya
S
D000818:Animals; D001943:Breast Neoplasms; D002292:Carcinoma, Renal Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D005260:Female; D005290:Ferric Compounds / Q000633:toxicity; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D017403:In Situ Hybridization; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009566:Nitrates / Q000633:toxicity; D009928:Organ Specificity; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
D005290:Ferric Compounds; D035683:MicroRNAs; D009566:Nitrates; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C025302:ferric nitrate