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Naohiko Seki - One of the best experts on this subject based on the ideXlab platform.
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Dual strands of the Mir-145 duplex (Mir-145-5p and Mir-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis
Journal of Human Genetics, 2018Co-Authors: Shunsuke Misono, Naohiko Seki, Keiko Mizuno, Yasutaka Yamada, Akifumi Uchida, Takayuki Arai, Tomohiro Kumamoto, Hiroki Sanada, Takayuki Suetsugu, Hiromasa InoueAbstract:Our original microRNA (miRNA) expression signatures (based on RNA sequencing) revealed that both strands of the Mir-145 duplex ( Mir-145-5p , the guide strand, and Mir-145-3p , the passenger strand) were downregulated in several types of cancer tissues. Involvement of passenger strands of miRNAs in cancer pathogenesis is a new concept in miRNA biogenesis. In our continuing analysis of lung adenocarcinoma (LUAD) pathogenesis, we aimed here to identify important oncogenes that were controlled by Mir-145-5p and Mir-145-3p . Downregulation of Mir-145-5p and Mir-145-3p was confirmed in LUAD clinical specimens. Functional assays showed that Mir-145-3p significantly blocked the malignant abilities in LUAD cells, e.g., cancer cell proliferation, migration and invasion. Thus, the data showed that expression of the passenger strand of the Mir-145 -duplex acted as an anti-tumor miRNA. In LUAD cells, we identified four possible target genes ( LMNB2 , NLN , SIX4 , and DDC ) that might be regulated by both strands of Mir-145 . Among the possible targets, high expression of LMNB2 predicted a significantly poorer prognosis of LUAD patients (disease-free survival, p = 0.0353 and overall survival, p = 0.0017). Overexpression of LMNB2 was detected in LUAD clinical specimens and its aberrant expression promoted malignant transformation of LUAD cells. Genes regulated by anti-tumor Mir-145-5p and Mir-145-3p are closely involved in the molecular pathogenesis of LUAD. We suggest that they are promising prognostic markers for this disease. Our approach, based on the roles of anti-tumor miRNAs, will contribute to improved understanding of the molecular pathogenesis of LUAD.
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Dual-strand tumor-suppressor microRNA-145 (Mir-145-5p and Mir-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma.
Oncotarget, 2016Co-Authors: Hiroko Mataki, Yusuke Goto, Naohiko Seki, Keiko Mizuno, Tomohiro Kumamoto, Nijiro Nohata, Kazuto Kamikawaji, Keiichi Koshizuka, Hiromasa InoueAbstract:// Hiroko Mataki 1 , Naohiko Seki 2 , Keiko Mizuno 1 , Nijiro Nohata 3 , Kazuto Kamikawaji 1 , Tomohiro Kumamoto 1 , Keiichi Koshizuka 2 , Yusuke Goto 2 , Hiromasa Inoue 1 1 Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520 Japan 2 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, 260-8670 Japan 3 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA Correspondence to: Naohiko Seki, email: naoseki@faculty.chiba-u.jp Keywords: microRNA-145-5p , microR-145-3p , tumor-suppressor, MTDH , lung squamous cell carcinoma Received: June 11, 2016 Accepted: August 26, 2016 Published: September 27, 2016 ABSTRACT Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that Mir-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of Mir-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of Mir-145-5p and Mir-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both Mir-145-3p as well as Mir-145-5p acted as antitumor miRNAs. We identified seven putative target genes ( MTDH , EPN3 , TPD52 , CYP27B1 , LMAN1 , STAT1 and TXNDC12 ) that were coordinately regulated by Mir-145-5p and Mir-145-3p in lung SCC. Among the seven genes, we found that metadherin ( MTDH ) was a direct target of these miRNAs. Kaplan–Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of Mir-145 , Mir-145-5p and Mir-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.
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Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 ( Mir-145-5p and Mir-145-3p ): inhibition of bladder cancer cell aggressiveness
Oncotarget, 2016Co-Authors: Ryosuke Matsushita, Yusuke Goto, Hirofumi Yoshino, Hideki Enokida, Masayuki Nakagawa, Kazutaka Miyamoto, Masaya Yonemori, Satoru Inoguchi, Naohiko SekiAbstract:// Ryosuke Matsushita 1 , Hirofumi Yoshino 1 , Hideki Enokida 1 , Yusuke Goto 2 , Kazutaka Miyamoto 1 , Masaya Yonemori 1 , Satoru Inoguchi 1 , Masayuki Nakagawa 1 , Naohiko Seki 2 1 Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan 2 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan Correspondence to: Naohiko Seki, e-mail: naoseki@faculty.chiba-u.jp Keywords: Mir-145-5p, Mir-145-3p, tumor-suppressor, UHRF1, bladder cancer Received: February 22, 2016 Accepted: March 28, 2016 Published: April 09, 2016 ABSTRACT In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA ( miR ) -145-5p (guide-strand) and Mir-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that Mir-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of Mir-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of Mir-145-3p and BC oncogenic pathways and targets regulated by Mir-145-5p/Mir-145-3p . Ectopic expression of either Mir-145-5p or Mir-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 ( UHRF1 ) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of Mir-145 ( Mir-145-5p : guide-strand and Mir-145-3p : passenger-strand) play pivotal roles in BC cells by regulating UHRF1 . The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies.
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tumor suppressive microrna 143 145 cluster targets hexokinase 2 in renal cell carcinoma
Cancer Science, 2013Co-Authors: Hirofumi Yoshino, Satoko Kojima, Shuichi Tatarano, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Masayuki Nakagawa, Naohiko SekiAbstract:Our recent studies of microRNA (miRNA) expression signatures have indicated that the miR-143/145 cluster is significantly downregulated in several types of cancer and represents a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in cancer cells and to identify novel molecular targets of the miR-143/145 cluster in renal cell carcinoma (RCC). The expression levels of miR-143 and Mir-145 were significantly downregulated in RCC tissues compared with adjacent non-cancerous tissues. A significant positive correlation was recognized between miR-143 and Mir-145 expression. Restoration of mature miR-143 or Mir-145 in 786-O and A498 RCC cells revealed that both mature miRNAs significantly inhibited cancer cell proliferation and invasion, suggesting that the miR-143/145 cluster functioned as a tumor suppressor in RCC. Gene expression data and in silico database analysis showed that the hexokinase-2 (HK2) gene, which encodes a glycolytic enzyme crucial for the Warburg effect in cancer cells, was a candidate target of the miR-143/145 cluster. Luciferase reporter assays showed that both miR-143 and Mir-145 directly regulated HK2. In RCC clinical specimens, the expression of HK2 was significantly higher in cancer tissues than in non-cancerous tissues. Silencing HK2 suppressed RCC cell proliferation and invasion, suggesting that HK2 has oncogenic functions in RCC. Thus, our data showed that loss of the tumor-suppressive miR-143/145 cluster enhanced RCC cell proliferation and invasion through targeting HK2.
Yusuke Goto - One of the best experts on this subject based on the ideXlab platform.
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RNA sequencing-based microRNA expression signature in esophageal squamous cell carcinoma: oncogenic targets by antitumor miR-143-5p and miR-143-3p regulation
Journal of Human Genetics, 2020Co-Authors: Masumi Wada, Yusuke Goto, Takako Tanaka, Reona Okada, Shogo Moriya, Tetsuya Idichi, Masahiro Noda, Ken Sasaki, Yoshiaki Kita, Hiroshi KuraharaAbstract:Aberrantly expressed microRNAs (miRNAs) disrupt intracellular RNA networks and contribute to malignant transformation of cancer cells. Utilizing the latest RNA sequencing technology, we newly created the miRNA expression signature of esophageal squamous cell carcinoma (ESCC). A total of 47 miRNAs were downregulated in ESCC tissues, and these miRNAs were candidates for antitumor miRNAs in ESCC cells. Analysis of the signature revealed that several passenger strands of miRNAs were significantly downregulated in ESCC, e.g., miR-28-3p , miR-30a-3p , miR-30c-3p , miR-133a-3p , miR-139-3p , miR-143-5p , and Mir-145-3p . Recent studies indicate that some passenger strands of miRNAs closely involved in cancer pathogenesis. In this study, we focused on both strands of pre- miR-143 , and investigated their antitumor roles and target oncogenes in ESCC. Ectopic expression of miR-143-5p and miR-143-3p significantly attenuated malignant phenotypes (e.g., proliferation, migration, and invasive abilities) in ESCC cell lines. We revealed that six genes ( HN1 , HMGA2 , NETO2 , STMN1 , TCF3 , and MET ) were putative targets of miR-143-5p regulation, and one gene ( KRT80 ) was a putative target of miR-143-3p regulation in ESCC cells. Our ESCC miRNA signature and analysis strategy provided important insights into the molecular pathogenesis of ESCC.
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Dual-strand tumor-suppressor microRNA-145 (Mir-145-5p and Mir-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma.
Oncotarget, 2016Co-Authors: Hiroko Mataki, Yusuke Goto, Naohiko Seki, Keiko Mizuno, Tomohiro Kumamoto, Nijiro Nohata, Kazuto Kamikawaji, Keiichi Koshizuka, Hiromasa InoueAbstract:// Hiroko Mataki 1 , Naohiko Seki 2 , Keiko Mizuno 1 , Nijiro Nohata 3 , Kazuto Kamikawaji 1 , Tomohiro Kumamoto 1 , Keiichi Koshizuka 2 , Yusuke Goto 2 , Hiromasa Inoue 1 1 Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8520 Japan 2 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, 260-8670 Japan 3 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA Correspondence to: Naohiko Seki, email: naoseki@faculty.chiba-u.jp Keywords: microRNA-145-5p , microR-145-3p , tumor-suppressor, MTDH , lung squamous cell carcinoma Received: June 11, 2016 Accepted: August 26, 2016 Published: September 27, 2016 ABSTRACT Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that Mir-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of Mir-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of Mir-145-5p and Mir-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both Mir-145-3p as well as Mir-145-5p acted as antitumor miRNAs. We identified seven putative target genes ( MTDH , EPN3 , TPD52 , CYP27B1 , LMAN1 , STAT1 and TXNDC12 ) that were coordinately regulated by Mir-145-5p and Mir-145-3p in lung SCC. Among the seven genes, we found that metadherin ( MTDH ) was a direct target of these miRNAs. Kaplan–Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of Mir-145 , Mir-145-5p and Mir-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.
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Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 ( Mir-145-5p and Mir-145-3p ): inhibition of bladder cancer cell aggressiveness
Oncotarget, 2016Co-Authors: Ryosuke Matsushita, Yusuke Goto, Hirofumi Yoshino, Hideki Enokida, Masayuki Nakagawa, Kazutaka Miyamoto, Masaya Yonemori, Satoru Inoguchi, Naohiko SekiAbstract:// Ryosuke Matsushita 1 , Hirofumi Yoshino 1 , Hideki Enokida 1 , Yusuke Goto 2 , Kazutaka Miyamoto 1 , Masaya Yonemori 1 , Satoru Inoguchi 1 , Masayuki Nakagawa 1 , Naohiko Seki 2 1 Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan 2 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan Correspondence to: Naohiko Seki, e-mail: naoseki@faculty.chiba-u.jp Keywords: Mir-145-5p, Mir-145-3p, tumor-suppressor, UHRF1, bladder cancer Received: February 22, 2016 Accepted: March 28, 2016 Published: April 09, 2016 ABSTRACT In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA ( miR ) -145-5p (guide-strand) and Mir-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that Mir-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of Mir-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of Mir-145-3p and BC oncogenic pathways and targets regulated by Mir-145-5p/Mir-145-3p . Ectopic expression of either Mir-145-5p or Mir-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 ( UHRF1 ) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of Mir-145 ( Mir-145-5p : guide-strand and Mir-145-3p : passenger-strand) play pivotal roles in BC cells by regulating UHRF1 . The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies.
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The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer
Journal of Human Genetics, 2014Co-Authors: Satoko Kojima, Miki Fuse, Yusuke Goto, Rika Nishikawa, Hirofumi Yoshino, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Yukio NayaAbstract:Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 ( miR-143/145 ) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or Mir-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 ( GOLM1 ) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1 . Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.
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the tumor suppressive microrna 143 145 cluster inhibits cell migration and invasion by targeting golm1 in prostate cancer
Journal of Human Genetics, 2014Co-Authors: Satoko Kojima, Miki Fuse, Yusuke Goto, Rika Nishikawa, Hirofumi Yoshino, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Yukio NayaAbstract:Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 (miR-143/145) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or Mir-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 (GOLM1) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1. Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.
Yukihiro Akao - One of the best experts on this subject based on the ideXlab platform.
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Downregulation of anti-oncomirs miR-143/145 cluster occurs before APC gene aberration in the development of colorectal tumors
Medical Molecular Morphology, 2013Co-Authors: Akemi Kamatani, Yoshihito Nakagawa, Yukihiro Akao, Naoko Maruyama, Mitsuo Nagasaka, Tomoyuki Shibata, Tomomitsu Tahara, Ichiro HirataAbstract:Accumulating data indicate that some microRNAs (miRNAs or miRs) can function as tumor suppressors or oncogenes and as such are important in cancer development. We previously reported that miR-143 and -145 are frequently downregulated in colon adenomas and cancers, acting as tumor suppressors. In this present study, we investigated the relationship between the downregulation of the miR-143/145 cluster and genetic aberrations of adenomatous polyposis coli ( APC ), which are early genetic events in the development of colorectal tumors. The expression levels of both miRs were determined by performing real-time PCR on tissue samples of familial adenomatous polyposis (FAP), colorectal adenoma, colorectal cancer, and paired non-tumorous tissues. Also, the expression of C- or N-terminus of the APC protein and that of the p53 protein in these tissues were examined immunohistochemically. Our data clearly indicated that the decreased expression of miR-143 and -145 frequently occurred before APC gene aberrations. The downregulation of miR-143 and -145 is thus an important genetic event for the initiation step in colorectal tumor development.
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replacement treatment with microrna 143 and 145 induces synergistic inhibition of the growth of human bladder cancer cells by regulating pi3k akt and mapk signaling pathways
Cancer Letters, 2013Co-Authors: Shunsuke Noguchi, Nami Yamada, Yuki Yasui, Junya Iwasaki, Minami Kumazaki, Seiji Naito, Yukihiro AkaoAbstract:Abstract We recently reported that both microRNA (miR)-143 and -145 are downregulated in human bladder cancer T24 cells and that miR-143 targets ERK5 . In this study, we assessed the anti-tumor effects of combination treatment with miR-143 and -145 on bladder cancer cell lines T24, SNK57, and NKB1, in which the expression levels of miR-143 and -145 are downregulated. The ectopic expression of both miR-143 and -145 led to a significantly synergistic growth inhibition of T24 and NKB1 cells, but not that of SNK57 cells with the levels of miR-143 and -145 higher than those in T24 and NKB1 cells. The MAPK signaling pathway in NKB1 cells and both PI3K/Akt and MAPK signaling pathways in T24 cells were synergistically repressed by the co-treatment with miR-143 and -145. We newly elucidated that miR-143 targeted akt and that Mir-145 targeted integrin-linked kinase ( ilk ) in T24 cells based on the results of a luciferase activity assay. Silencing of ilk significantly inhibited the growth of all the bladder cancer cells tested. Also, the level of phosphorylated ERK1/2 in T24 cells and that of phosphorylated Akt in SNK57 and NKB1 cells were decreased by ilk silencing. This study has provided novel important evidence with regard to the functions of anti-oncogenic miR-143 and -145 and also suggests the possible use of miR-143 and -145 for combination replacement therapy in cancers in which both miRNAs are downregulated.
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microrna 143 functions as a tumor suppressor in human bladder cancer t24 cells
Cancer Letters, 2011Co-Authors: Syunsuke Noguchi, Yuki Hoshino, Kohji Maruo, Nami Yamada, Yukio Kitade, Tomoki Naoe, Takashi Mori, Yukihiro AkaoAbstract:MicroRNA (miR)-143 and -145 were down-regulated in human bladder cancer T24 cells. The enforced expression of miR-143 induced growth-suppression in T24 cells through down-regulation of ERK5 and Akt expression at translational level, and chemically-modified synthetic miR-143 (miR-143/BP) exhibited a greater growth inhibitory effect than wild-type miR-143. In addition, the synthetic miR-143/BP induced apoptotic cell death in some of the transfected cells. Furthermore, co-treatment with the synthetic miR-143/BP and cisplatin showed the additive growth-suppressing effect on T24 cells. These findings suggest that the chemically-modified synthetic miR-143 functions as a tumor suppressor in T24 cells by targeting ERK5 and/or Akt.
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MicroRNAs and their therapeutic potential for human diseases: microRNAs, miR-143 and -145, function as anti-oncomirs and the application of chemically modified miR-143 as an anti-cancer drug.
Journal of pharmacological sciences, 2010Co-Authors: Yukio Kitade, Yukihiro AkaoAbstract:We examined the expression levels of microRNAs (miRNAs; miRs) in colorectal tumors (63 cancer specimens and 65 adenoma specimens) compared to adjacent non-tumorous tissues. Decreased expression of miR-143 and -145 was frequently observed in the adenoma and cancer samples. As the down-regulation of miR-143 and -145 was observed even in the early phase of adenoma formation, their decreased expression would appear to contribute mainly to the initiation of tumorigenesis. For clinical application, we added aromatic benzene-pyridine (BP-type) analogs to the 3'-overhang region of the RNA-strand and changed the sequences of the passenger strand in the miR-143 duplex (miR-143BPs), leading to greater activity and increased resistance to nuclease. The cell growth inhibitory effect of the chemically modified miR-143BPx in vitro was greater than that of the endogenous miR-143. The modified miR-143BPx showed a significant tumor-suppressive effect on xenografted tumors of human colorectal cancer DLD-1 cells. These findings suggest that miR-143 and -145 are important onco-related genes for the initiation of colorectal tumor development and that chemically modified miR-143BPx may be a candidate for an RNA medicine for the treatment of colorectal tumors.
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decreased expression of microrna 143 and 145 in human gastric cancers
Oncology, 2009Co-Authors: Takeshi Takagi, Yoshihito Nakagawa, Nobuhiko Tanigawa, Tomoki Naoe, Yukihiro AkaoAbstract:Objective: Downregulation of specific microRNAs (miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. We investigated the role of the miRNAs miR-143 and Mir-145 in gastric cancers. Methods: The expression levels of miR-143 and Mir-145 in the samples from 43 patients with gastric cancer were determined by real-time PCR using TaqMan assay. The growth inhibitory effect was estimated by the transfection of human gastric cancer cells with the miRNA. Results: The expression levels of miR-143 and -145 were decreased in most human gastric cancers examined, as previously reported to occur in colon tumors. The transfection of human gastric MKN-1 cells with Mir-145 resulted in a greater growth inhibitory effect than that with miR-143, results which were contrary to those in colon cancers. In MKN-1 cells, an additive effect on growth inhibition was shown by the combined transfection with miR-143 and Mir-145; further, higher sensitivity to 5-fluorouracil was also observed following the transfection with miR-143 or Mir-145. The possible candidate target messenger RNAs of Mir-145 were identified to be insulin receptor substrate-1 and β-actin. Conclusion: Taken together, these findings suggest that miR-143 and Mir-145 act as anti-oncomirs common to gastrointestinal tumors.
Hirofumi Yoshino - One of the best experts on this subject based on the ideXlab platform.
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Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 ( Mir-145-5p and Mir-145-3p ): inhibition of bladder cancer cell aggressiveness
Oncotarget, 2016Co-Authors: Ryosuke Matsushita, Yusuke Goto, Hirofumi Yoshino, Hideki Enokida, Masayuki Nakagawa, Kazutaka Miyamoto, Masaya Yonemori, Satoru Inoguchi, Naohiko SekiAbstract:// Ryosuke Matsushita 1 , Hirofumi Yoshino 1 , Hideki Enokida 1 , Yusuke Goto 2 , Kazutaka Miyamoto 1 , Masaya Yonemori 1 , Satoru Inoguchi 1 , Masayuki Nakagawa 1 , Naohiko Seki 2 1 Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan 2 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan Correspondence to: Naohiko Seki, e-mail: naoseki@faculty.chiba-u.jp Keywords: Mir-145-5p, Mir-145-3p, tumor-suppressor, UHRF1, bladder cancer Received: February 22, 2016 Accepted: March 28, 2016 Published: April 09, 2016 ABSTRACT In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA ( miR ) -145-5p (guide-strand) and Mir-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that Mir-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of Mir-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of Mir-145-3p and BC oncogenic pathways and targets regulated by Mir-145-5p/Mir-145-3p . Ectopic expression of either Mir-145-5p or Mir-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 ( UHRF1 ) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of Mir-145 ( Mir-145-5p : guide-strand and Mir-145-3p : passenger-strand) play pivotal roles in BC cells by regulating UHRF1 . The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies.
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The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer
Journal of Human Genetics, 2014Co-Authors: Satoko Kojima, Miki Fuse, Yusuke Goto, Rika Nishikawa, Hirofumi Yoshino, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Yukio NayaAbstract:Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 ( miR-143/145 ) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or Mir-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 ( GOLM1 ) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1 . Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.
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the tumor suppressive microrna 143 145 cluster inhibits cell migration and invasion by targeting golm1 in prostate cancer
Journal of Human Genetics, 2014Co-Authors: Satoko Kojima, Miki Fuse, Yusuke Goto, Rika Nishikawa, Hirofumi Yoshino, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Yukio NayaAbstract:Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 (miR-143/145) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or Mir-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 (GOLM1) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1. Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.
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tumor suppressive microrna 143 145 cluster targets hexokinase 2 in renal cell carcinoma
Cancer Science, 2013Co-Authors: Hirofumi Yoshino, Satoko Kojima, Shuichi Tatarano, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Masayuki Nakagawa, Naohiko SekiAbstract:Our recent studies of microRNA (miRNA) expression signatures have indicated that the miR-143/145 cluster is significantly downregulated in several types of cancer and represents a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in cancer cells and to identify novel molecular targets of the miR-143/145 cluster in renal cell carcinoma (RCC). The expression levels of miR-143 and Mir-145 were significantly downregulated in RCC tissues compared with adjacent non-cancerous tissues. A significant positive correlation was recognized between miR-143 and Mir-145 expression. Restoration of mature miR-143 or Mir-145 in 786-O and A498 RCC cells revealed that both mature miRNAs significantly inhibited cancer cell proliferation and invasion, suggesting that the miR-143/145 cluster functioned as a tumor suppressor in RCC. Gene expression data and in silico database analysis showed that the hexokinase-2 (HK2) gene, which encodes a glycolytic enzyme crucial for the Warburg effect in cancer cells, was a candidate target of the miR-143/145 cluster. Luciferase reporter assays showed that both miR-143 and Mir-145 directly regulated HK2. In RCC clinical specimens, the expression of HK2 was significantly higher in cancer tissues than in non-cancerous tissues. Silencing HK2 suppressed RCC cell proliferation and invasion, suggesting that HK2 has oncogenic functions in RCC. Thus, our data showed that loss of the tumor-suppressive miR-143/145 cluster enhanced RCC cell proliferation and invasion through targeting HK2.
Hideki Enokida - One of the best experts on this subject based on the ideXlab platform.
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Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 ( Mir-145-5p and Mir-145-3p ): inhibition of bladder cancer cell aggressiveness
Oncotarget, 2016Co-Authors: Ryosuke Matsushita, Yusuke Goto, Hirofumi Yoshino, Hideki Enokida, Masayuki Nakagawa, Kazutaka Miyamoto, Masaya Yonemori, Satoru Inoguchi, Naohiko SekiAbstract:// Ryosuke Matsushita 1 , Hirofumi Yoshino 1 , Hideki Enokida 1 , Yusuke Goto 2 , Kazutaka Miyamoto 1 , Masaya Yonemori 1 , Satoru Inoguchi 1 , Masayuki Nakagawa 1 , Naohiko Seki 2 1 Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan 2 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan Correspondence to: Naohiko Seki, e-mail: naoseki@faculty.chiba-u.jp Keywords: Mir-145-5p, Mir-145-3p, tumor-suppressor, UHRF1, bladder cancer Received: February 22, 2016 Accepted: March 28, 2016 Published: April 09, 2016 ABSTRACT In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA ( miR ) -145-5p (guide-strand) and Mir-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that Mir-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of Mir-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of Mir-145-3p and BC oncogenic pathways and targets regulated by Mir-145-5p/Mir-145-3p . Ectopic expression of either Mir-145-5p or Mir-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 ( UHRF1 ) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of Mir-145 ( Mir-145-5p : guide-strand and Mir-145-3p : passenger-strand) play pivotal roles in BC cells by regulating UHRF1 . The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies.
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The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer
Journal of Human Genetics, 2014Co-Authors: Satoko Kojima, Miki Fuse, Yusuke Goto, Rika Nishikawa, Hirofumi Yoshino, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Yukio NayaAbstract:Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 ( miR-143/145 ) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or Mir-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 ( GOLM1 ) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1 . Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.
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the tumor suppressive microrna 143 145 cluster inhibits cell migration and invasion by targeting golm1 in prostate cancer
Journal of Human Genetics, 2014Co-Authors: Satoko Kojima, Miki Fuse, Yusuke Goto, Rika Nishikawa, Hirofumi Yoshino, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Yukio NayaAbstract:Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 (miR-143/145) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or Mir-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 (GOLM1) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1. Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.
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tumor suppressive microrna 143 145 cluster targets hexokinase 2 in renal cell carcinoma
Cancer Science, 2013Co-Authors: Hirofumi Yoshino, Satoko Kojima, Shuichi Tatarano, Toshihiko Itesako, Hideki Enokida, Takeshi Chiyomaru, Takashi Kinoshita, Masayuki Nakagawa, Naohiko SekiAbstract:Our recent studies of microRNA (miRNA) expression signatures have indicated that the miR-143/145 cluster is significantly downregulated in several types of cancer and represents a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in cancer cells and to identify novel molecular targets of the miR-143/145 cluster in renal cell carcinoma (RCC). The expression levels of miR-143 and Mir-145 were significantly downregulated in RCC tissues compared with adjacent non-cancerous tissues. A significant positive correlation was recognized between miR-143 and Mir-145 expression. Restoration of mature miR-143 or Mir-145 in 786-O and A498 RCC cells revealed that both mature miRNAs significantly inhibited cancer cell proliferation and invasion, suggesting that the miR-143/145 cluster functioned as a tumor suppressor in RCC. Gene expression data and in silico database analysis showed that the hexokinase-2 (HK2) gene, which encodes a glycolytic enzyme crucial for the Warburg effect in cancer cells, was a candidate target of the miR-143/145 cluster. Luciferase reporter assays showed that both miR-143 and Mir-145 directly regulated HK2. In RCC clinical specimens, the expression of HK2 was significantly higher in cancer tissues than in non-cancerous tissues. Silencing HK2 suppressed RCC cell proliferation and invasion, suggesting that HK2 has oncogenic functions in RCC. Thus, our data showed that loss of the tumor-suppressive miR-143/145 cluster enhanced RCC cell proliferation and invasion through targeting HK2.