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論文 |
論文
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Shiraishi, Kouya ; Okada, Yukinori ; Takahashi, Atsushi ; Kamatani, Yoichiro ; Momozawa, Yukihide ; Ashikawa, Kyota ; Kunitoh, Hideo ; Matsumoto, Shingo ; Takano, Atsushi ; Shimizu, Kimihiro ; Goto, Akiteru ; Tsuta, Koji ; Watanabe, Shun-ichi ; Ohe, Yuichiro ; Watanabe, Yukio ; Goto, Yasushi ; Nokihara, Hiroshi ; Furuta, Koh ; Yoshida, Akihiko ; Goto, Koichi ; Hishida, Tomoyuki ; Tsuboi, Masahiro ; Tsuchihara, Katsuya ; Miyagi, Yohei ; Tanaka, Kazumi ; Nakayama, Haruhiko ; Yokose, Tomoyuki ; Nagashima, Toshiteru ; Ohtaki, Yoichi ; Maeda, Daichi ; Imai, Kazuhiro ; Minamiya, Yoshihiro ; Sakamoto, Hiromi ; Saito, Akira ; Shimada, Yoko ; Sunami, Kuniko ; Saito, Motonobu ; Inazawa, Johji ; Nakamura, Yusuke ; Yoshida, Teruhiko ; Yokota, Jun ; Matsuda, Fumihiko ; Matsuo, Keitaro ; Daigo, Yataro ; Kubo, Michiaki ; Kohno, Takashi ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than
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in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10 '17, per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10 '9, per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations.
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論文
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Goto, Akiteru ; Masamitsu, Tanaka ; Yoshida, Makoto ; Umakoshi, Michinobu ; Nanjo, Hiroshi ; Shiraishi, Kouya ; Saito, Motonobu ; Kohno, Takashi ; Kuriyama, Sei ; Konno, Hayato ; Imai, Kazuhiro ; Hajime, Saito ; Minamiya, Yoshihiro ; Maeda, Daichi ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Purpose miR-451 is a tumor suppressive microRNA with several target genes, including Macrophage migr
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ation inhibitory factor (MIF). As little is known about the expression and clinicopathological significance of mir-451 in NSCLC, we performed a clinicopathological study of 370 NSCLC cases to clarify them. Cell biological experiments were also performed on NSCLC cell lines to confirm the tumor-suppressive role of miR-451 and whether or not MIF is targeted by miR-451. Methods We analyzed 370 NSCLC cases for the miR-451 expression by quantitative real-time polymerase chain reaction and the MIF expression by immunohistochemistry. Eighty-four background lung tissue samples were also evaluated for the miR-451 expression. The clinicopathological and genetic factors surveyed were the disease-free survival, smoking status, histological type, disease stage, EGFR gene mutations and ALK rearrangements. In 286 adenocarcinoma cases, the invasive status (adenocarcinoma in situ, minimally invasive adenocarcinoma and invasive adenocarcinoma) was also evaluated. Five NSCLC cell lines (H23, H441, H522, H1703, and H1975) were cultured and evaluated for their miR-451 and MIF expression. The cell lines with lower miR-451 and higher MIF expressions were then selected and transfected with miR-451-mimic to observe its effects on MIF expression, Akt and Erk status, cell proliferation, and cell migration. Results The miR-451 expression was down-regulated in cancer tissues compared with background lung tissues (P<0.0001). Factors such as advanced disease stage, positive pleural invasion and nodal status and being a smoker were significantly correlated with a lower expression of miR-451 (P<0.05 each), while EGFR gene mutations and ALK rearrangements were not. In adenocarcinoma, invasive and minimally invasive adenocarcinoma showed lower expression of miR-451 than adenocarcinoma in situ (P<0.0005, respectively). A survival analysis showed that a lower expression of miR-451 was an independent predictor of a poor prognosis for NSCLC (P<0.05). The MIF expression was inversely correlated with the miR-451 expression. Out of 5 NSCLC cell lines examined, H441 and H1975 showed higher MIF and lower miR-451 expressions. After the transfection of miR-451-mimic, the MIF expression and phosphorylated Akt expression of these cell lines was suppressed, as were cell proliferation and cell migration. Conclusion This clinicopathological study of 370 NSCLC cases and the cell biological studies of NSCLC cell lines clarified the tumor-suppressive role of miR-451 and its prognostic value. We also validated MIF as a target of miR-451 in NSCLC. © 2017 Goto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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