Downregulation of the micro RNA biogenesis components and its association with poor prognosis in hepatocellular carcinoma

• Published in: Cancer science 2013-05, Vol.104 (5), p.543-551
• Main Authors: Kitagawa, Noriyuki, Ojima, Hidenori, Shirakihara, Takuya, Shimizu, Hiroko, Kokubu, Akiko, Urushidate, Tomoko, Totoki, Yasushi, Kosuge, Tomoo, Miyagawa, Shinichi, Shibata, Tatsuhiro
• Format: Article
• Language: English
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12126

Genetic alterations and deregulation of the mi RNA biogenesis pathway components have been reported in human tumors. Tissue‐specific deletion of the D icer gene, which encodes an essential mi RNA processing enzyme, promotes carcinogenesis in animal models. These features indicate that aberrant mi RNA biogenesis components are directly associated with cancer. For the present study, we conducted quantitative RT ‐ PCR of 14 genes that are related to the mi RNA biogenesis pathway in 47 paired samples of primary hepatocellular carcinoma ( HCC ) and matched non‐cancerous liver. Expression of seven genes ( D gcr8, p68, p72, D icer, A go3, A go4 and P iwil4) was significantly decreased in primary HCC , especially in non‐viral HCC subtypes, compared to the non‐cancerous liver. Combinations of decreased expression of the mi RNA biogenesis components in non‐cancerous liver were related to cigarette smoking, alcohol intake and diabetes, which are known to be risk factors for HCC , and were also associated with the occurrence of multicentric tumors. Reduction of two of these genes ( D icer and p68) in HCC was associated with poor prognosis. Trimethylation of histone H 3 lysine 27 in the promoters is implicated in the deregulation of these mi RNA ‐biogenesis‐related genes in non‐ HBV genome integrated HCC cell lines. In conclusion, deregulation of the mi RNA biogenesis pathway components is frequently observed in non‐viral‐associated HCC and is linked to etiological risk factors and poor prognosis. Our study further showed that epigenetic regulation could be implicated in the deregulation of these genes during hepatocarcinogenesis.