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1.
Tumor‐suppressive microRNA‐223 inhibits cancer cell migration and invasion by targeting ITGA3/ITGB1 signaling in prostate cancer
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Akira Kurozumi Yusuke Goto Ryosuke Matsushita Ichiro Fukumoto Mayuko Kato Rika Nishikawa Shinichi Sakamoto Hideki Enokida Masayuki Nakagawa Tomohiko Ichikawa Naohiko Seki 《Cancer science》2016,107(1):84-94
Analysis of microRNA (miRNA) expression signatures in prostate cancer (PCa) and castration‐resistant PCa has revealed that miRNA‐223 is significantly downregulated in cancer tissues, suggesting that miR‐223 acts as a tumor‐suppressive miRNA by targeting oncogenes. The aim of this study was to investigate the functional roles of miR‐223 and identify downstream oncogenic targets regulated by miR‐223 in PCa cells. Functional studies of miR‐223 were carried out to investigate cell proliferation, migration, and invasion using PC3 and PC3M PCa cell lines. Restoration of miR‐223 significantly inhibited cancer cell migration and invasion in PCa cells. In silico database and genome‐wide gene expression analyses revealed that ITGA3 and ITGB1 were direct targets of miR‐223 regulation. Knockdown of ITGA3 and ITGB1 significantly inhibited cancer cell migration and invasion in PCa cells by regulating downstream signaling. Moreover, overexpression of ITGA3 and ITGB1 was observed in PCa clinical specimens. Thus, our data indicated that downregulation of miR‐223 enhanced ITGA3/ITGB1 signaling and contributed to cancer cell migration and invasion in PCa cells. Elucidation of the molecular pathways modulated by tumor‐suppressive miRNAs provides insights into the mechanisms of PCa progression and metastasis. 相似文献
2.
Takeshi Yamasaki Naohiko Seki Hirofumi Yoshino Toshihiko Itesako Yasutoshi Yamada Shuichi Tatarano Hideo Hidaka Tomokazu Yonezawa Masayuki Nakagawa Hideki Enokida 《Cancer science》2013,104(11):1411-1419
Our recent studies of microRNA (miRNA) expression signatures demonstrated that microRNA‐1291 (miR‐1291) was significantly downregulated in renal cell carcinoma (RCC) clinical specimens and was a putative tumor‐suppressive miRNA in RCC. The aim of the present study was to investigate the functional significance of miR‐1291 in cancer cells and to identify novel miR‐1291‐mediated cancer pathways and target genes in RCC. Expression of miR‐1291 was significantly downregulated in RCC tissues compared with adjacent non‐cancerous tissues. Restoration of mature miR‐1291 in RCC cell lines (A498 and 786‐O) revealed significant inhibition of cell proliferation, migration and invasion, suggesting that miR‐1291 functioned as a tumor suppressor. To identify miR‐1291‐mediated molecular pathways and targets, we used gene expression analysis (expression of RCC clinical specimens and miR‐1291‐transfected A498 cells) and in silico database analysis. Our data demonstrated that 79 signaling pathways were significantly regulated by tumor‐suppressive miR‐1291 in RCC cells. Moreover, solute career family 2 member 1 (SLC2A1) was a candidate target of miR‐1291 regulation. The SLC2A1 gene provides instructions for producing glucose transporter protein type 1 (GLUT1). Luciferase reporter assays showed that miR‐1291 directly regulated SLC2A1/GLUT1. In RCC clinical specimens, the expression of SLC2A1/GLUT1 mRNA was significantly higher in cancer tissues than in non‐cancerous tissues. A significant inverse correlation was recognized between SLC2A1/GLUT1 and miR‐1291 expression (r = ?0.55, P < 0.0001). Loss of tumor‐suppressive miR‐1291 enhanced RCC cell proliferation, migration and invasion through targeting SLC2A1/GLUT1. The identification of novel tumor‐suppressive miR‐1291‐mediated molecular pathways and targets has provided new insights into RCC oncogenesis and metastasis. 相似文献
3.
Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre‐miR‐148a on gene regulation
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Tetsuya Idichi Naohiko Seki Hiroshi Kurahara Haruhi Fukuhisa Hiroko Toda Masataka Shimonosono Atsushi Okato Takayuki Arai Yoshiaki Kita Yuko Mataki Yuko kijima Kosei Maemura Shoji Natsugoe 《Cancer science》2018,109(6):2013-2026
We previously used RNA sequencing to establish the microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC). We found that both strands of pre‐miR‐148a (miR‐148a‐5p: the passenger strand and miR‐148a‐3p: the guide strand) were downregulated in cancer tissues. Ectopic expression of miR‐148a‐5p and miR‐148a‐3p significantly inhibited cancer cell migration and invasion, indicating that both strands of pre‐miR‐148a had tumor‐suppressive roles in PDAC cells. In silico database and genome‐wide gene expression analyses identified a total of 15 genes that were putative targets regulated by these miRNAs. High expression of miR‐148a‐5p targets (PHLDA2, LPCAT2 and AP1S3) and miR‐148a‐3p targets (SMA, ENDOD1 and UHMK1) was associated with poor prognosis of patients with PDAC. Moreover, knockdown of PHLDA2 expression inhibited cancer cell aggressiveness, suggesting PHLDA2 acted as an oncogene in PDAC cells. Involvement of the passenger strand of pre‐miR‐148a (miR‐148‐5p) is a new concept in cancer research. Novel approaches that identify tumor‐suppressive miRNA regulatory networks in lethal PDAC might provide new prognostic markers and therapeutic targets for this disease. 相似文献
4.
Hirofumi Yoshino Hideki Enokida Toshihiko Itesako Satoko Kojima Takashi Kinoshita Shuichi Tatarano Takeshi Chiyomaru Masayuki Nakagawa Naohiko Seki 《Cancer science》2013,104(12):1567-1574
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. 相似文献
5.
Dual tumor‐suppressors miR‐139‐5p and miR‐139‐3p targeting matrix metalloprotease 11 in bladder cancer
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Masaya Yonemori Naohiko Seki Hirofumi Yoshino Ryosuke Matsushita Kazutaka Miyamoto Masayuki Nakagawa Hideki Enokida 《Cancer science》2016,107(9):1233-1242
Our recent study of the microRNA (miRNA) expression signature of bladder cancer (BC) by deep‐sequencing revealed that two miRNA, microRNA‐139‐5p/microRNA‐139‐3p were significantly downregulated in BC tissues. The aim of this study was to investigate the functional roles of these miRNA and their modulation of cancer networks in BC cells. Functional assays of BC cells were performed using transfection of mature miRNA or small interfering RNA (siRNA). Genome‐wide gene expression analysis, in silico analysis and dual‐luciferase reporter assays were applied to identify miRNA targets. The associations between the expression of miRNA and its targets and overall survival were estimated by the Kaplan–Meier method. Gain‐of‐function studies showed that miR‐139‐5p and miR‐139‐3p significantly inhibited cell migration and invasion by BC cells. The matrix metalloprotease 11 gene (MMP11) was identified as a direct target of miR‐139‐5p and miR‐139‐3p. Kaplan–Meier survival curves showed that higher expression of MMP11 predicted shorter survival of BC patients (P = 0.029). Downregulated miR‐139‐5p or miR‐139‐3p enhanced BC cell migration and invasion in BC cells. MMP11 was directly regulated by these miRNA and might be a good prognostic marker for survival of BC patients. 相似文献
6.
Regulation of ITGA3 by the anti‐tumor miR‐199 family inhibits cancer cell migration and invasion in head and neck cancer
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Keiichi Koshizuka Toyoyuki Hanazawa Naoko Kikkawa Takayuki Arai Atsushi Okato Akira Kurozumi Mayuko Kato Koji Katada Yoshitaka Okamoto Naohiko Seki 《Cancer science》2017,108(8):1681-1692
For patients with head and neck squamous cell carcinoma (HNSCC), survival rates have not improved due to local recurrence and distant metastasis. Current targeted molecular therapies do not substantially benefit HNSCC patients. Therefore, it is necessary to use advanced genomic approaches to elucidate the molecular mechanisms underlying the aggressiveness of HNSCC cells. Analysis of our microRNA (miRNA) expression signature by RNA sequencing showed that the miR‐199 family (miR‐199a‐5p, miR‐199a‐3p, miR‐199b‐5p and miR‐199b‐3p) was significantly reduced in cancer tissues. Ectopic expression of mature miRNA demonstrated that all members of the miR‐199 family inhibited cancer cell migration and invasion by HNSCC cell lines (SAS and HSC3). These findings suggested that both passenger strands and guide strands of miRNA are involved in cancer pathogenesis. In silico database and genome‐wide gene expression analyses revealed that the gene coding for integrin α3 (ITGA3) was regulated by all members of the miR‐199 family in HNSCC cells. Knockdown of ITGA3 significantly inhibited cancer cell migration and invasion by HNSCC cells. Moreover, overexpression of ITGA3 was confirmed in HNSCC specimens, and high expression of ITGA3 predicted poorer survival of the patients (P = 0.0048). Our data revealed that both strands of pre‐miR‐199a (miR‐199a‐5p and miR‐199a‐3p) and pre‐miR‐199b (miR‐199b‐5p and miR‐199b‐3p) acted as anti‐tumor miRNA in HNSCC cells. Importantly, the involvement of passenger strand miRNA in the regulation of cellular processes is a novel concept in RNA research. Novel miRNA‐based approaches for HNSCC can be used to identify potential targets for the development of new therapeutic strategies. 相似文献
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Tumor‐suppressive microRNA‐145 induces growth arrest by targeting SENP1 in human prostate cancer cells
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Chunyang Wang Weiyang Tao Shaobin Ni Qiyin Chen Zhongshan Zhao Li Ma Yiming Fu Zhixing Jiao 《Cancer science》2015,106(4):375-382
Prostate cancer (PCa) prevails as the most commonly diagnosed malignancy in men and the third leading cause of cancer‐related deaths in developed countries. One of the distinct characteristics of prostate cancer is overexpression of the small ubiquitin‐like modifier (SUMO)‐specific protease 1 (SENP1), and the upregulation of SENP1 contributes to the malignant progression and cell proliferation of PCa. Previous studies have shown that the expression of microRNA‐145 (miRNA‐145) was extensively deregulated in PCa cell lines and primary clinical prostate cancer samples. Independent target prediction methods have indicated that the 3′‐untranslated region of SENP1 mRNA is a potential target of miR‐145. Here we found that low expression of miR‐145 was correlated with high expression of SENP1 in PCa cell line PC‐3. The transient introduction of miR‐145 caused cell cycle arrest in PC‐3 cells, and the opposite effect was observed when miR‐145 inhibitor was transfected. Further studies revealed that the SENP1 3′‐untranslated region was a regulative target of miR‐145 in vitro. MicroRNA‐145 also suppressed tumor formation in vivo in nude mice. Taken together, miR‐145 plays an important role in tumorigenesis of PCa through interfering SENP1. 相似文献
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Yasutoshi Yamada Hideo Hidaka Naohiko Seki Hirofumi Yoshino Takeshi Yamasaki Toshihiko Itesako Masayuki Nakagawa Hideki Enokida 《Cancer science》2013,104(3):304-312
Recently, many studies have suggested that microRNAs (miRNAs) are involved in cancer cell development, invasion, and metastasis of various types of human cancers. In a previous study, miRNA expression signatures from renal cell carcinoma (RCC) revealed that expression of microRNA‐135a (miR‐135a) was significantly reduced in cancerous tissues. The aim of this study was to investigate the functional significance of miR‐135a and to identify miR‐135a‐mediated molecular pathways in RCC cells. Restoration of mature miR‐135a significantly inhibited cancer cell proliferation and induced G0/G1 arrest in the RCC cell lines caki2 and A498, suggesting that miR‐135a functioned as a potential tumor suppressor. We then examined miR‐135a‐mediated molecular pathways using genome‐wide gene expression analysis and in silico analysis. A total of 570 downregulated genes were identified in miR‐135a transfected RCC cell lines. To investigate the biological significance of potential miR‐135a‐mediated pathways, we classified putative miR‐135a‐regulated genes according to the Kyoto Encyclopedia of Genes and Genomics pathway database. From our in silico analysis, 25 pathways, including the cell cycle, pathways in cancer, DNA replication, and focal adhesion, were significantly regulated by miR‐135a in RCC cells. Moreover, based on the results of this analysis, we investigated whether miR‐135a targeted the c‐MYC gene in RCC. Gain‐of‐function and luciferase reporter assays showed that c‐MYC was directly regulated by miR‐135a in RCC cells. Furthermore, c‐MYC expression was significantly upregulated in RCC clinical specimens. Our data suggest that elucidation of tumor‐suppressive miR‐135a‐mediated molecular pathways could reveal potential therapeutic targets in RCC. 相似文献
11.
Regulation of spindle and kinetochore‐associated protein 1 by antitumor miR‐10a‐5p in renal cell carcinoma
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Takayuki Arai Atsushi Okato Satoko Kojima Tetsuya Idichi Keiichi Koshizuka Akira Kurozumi Mayuko Kato Kazuto Yamazaki Yasuo Ishida Yukio Naya Tomohiko Ichikawa Naohiko Seki 《Cancer science》2017,108(10):2088-2101
Analysis of our original microRNA (miRNA) expression signature of patients with advanced renal cell carcinoma (RCC) showed that microRNA‐10a‐5p (miR‐10a‐5p) was significantly downregulated in RCC specimens. The aims of the present study were to investigate the antitumor roles of miR‐10a‐5p and the novel cancer networks regulated by this miRNA in RCC cells. Downregulation of miR‐10a‐5p was confirmed in RCC tissues and RCC tissues from patients treated with tyrosine kinase inhibitors (TKI). Ectopic expression of miR‐10a‐5p in RCC cell lines (786‐O and A498 cells) inhibited cancer cell migration and invasion. Spindle and kinetochore‐associated protein 1 (SKA1) was identified as an antitumor miR‐10a‐5p target by genome‐based approaches, and direct regulation was validated by luciferase reporter assays. Knockdown of SKA1 inhibited cancer cell migration and invasion in RCC cells. Overexpression of SKA1 was observed in RCC tissues and TKI‐treated RCC tissues. Moreover, analysis of The Cancer Genome Atlas database demonstrated that low expression of miR‐10a‐5p and high expression of SKA1 were significantly associated with overall survival in patients with RCC. These findings showed that downregulation of miR‐10a‐5p and overexpression of the SKA1 axis were highly involved in RCC pathogenesis and resistance to TKI treatment in RCC. 相似文献
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Long non‐coding RNA urothelial cancer‐associated 1 promotes bladder cancer cell migration and invasion by way of the hsa‐miR‐145–ZEB1/2–FSCN1 pathway
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Numerous studies suggest that several long non‐coding RNAs (lncRNAs) play critical roles in bladder cancer development and progression. Long non‐coding RNA urothelial cancer‐associated 1 (lncRNA‐UCA1) is highly expressed in bladder cancer tissues and cells, and it has been shown to play an important role in regulating aggressive phenotypes of bladder cancer cells. However, little is known about the molecular mechanism of lncRNA‐UCA1‐mediated bladder cancer cell migration and invasion. Here, we show that overexpression of lncRNA‐UCA1 could induce EMT and increase the migratory and invasive abilities of bladder cancer cells. Mechanistically, lncRNA‐UCA1 induced EMT of bladder cancer cells by upregulating the expression levels of zinc finger E‐box binding homeobox 1 and 2 (ZEB1 and ZEB2), and regulated bladder cancer cell migration and invasion by tumor suppressive hsa‐miR‐145 and its target gene the actin‐binding protein fascin homologue 1 (FSCN1). Furthermore, we also observed a positive correlation between lncRNA‐UCA1 and ZEB1/2 expression, and a negative correlation between lncRNA‐UCA1 and hsa‐miR‐145 expression in bladder cancer specimens. Importantly, we found that lncRNA‐UCA1 repressed hsa‐miR‐145 expression to upregulate ZEB1/2, whereas the suppression of hsa‐miR‐145 could upregulate lncRNA‐UCA1 expression in bladder cancer cells. Moreover, the binding site for hsa‐miR‐145 within exons 2 and 3 of lncRNA‐UCA1 contributed to the reciprocal negative regulation of lncRNA‐UCA1 and hsa‐miR‐145. Taken together, our results identified that lncRNA‐UCA1 enhances bladder cancer cell migration and invasion in part through the hsa‐miR‐145/ZEB1/2/FSCN1 pathway. Therefore, lncRNA‐UCA1 might act as a promising therapeutic target for the invasion and metastasis of bladder cancer. 相似文献
14.
Ken Yasukawa Lee Chuen Liew Keitaro Hagiwara Ai Hironaka‐Mitsuhashi Xian‐Yang Qin Yutaka Furutani Yasuhito Tanaka Hitoshi Nakagama Soichi Kojima Takashi Kato Takahiro Ochiya Luc Gailhouste 《Cancer science》2020,111(3):869-880
Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer‐related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR‐493‐5p, a major tumor suppressor miRNA that inactivates miR‐483‐3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR‐493‐5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR‐493‐5p given its significant inhibition through 3′‐UTR targeting in miR‐493‐5p‐rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR‐493‐5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR‐493‐5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR‐493‐5p activity. In summary, miR‐493‐5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies. 相似文献
15.
miR‐203 inhibits cell proliferation,invasion, and migration of non‐small‐cell lung cancer by downregulating RGS17
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Yongbin Chi Qinqin Jin Xinghui Liu Limin Xu Xiaoxue He Yan Shen Qiang Zhou Jue Zhang Mingming Jin 《Cancer science》2017,108(12):2366-2372
Involvement of the RGS17 oncogene in the promotion of non‐small‐cell lung cancer (NSCLC) has been reported, but the regulation mechanism in NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand the role of miRNAs in Regulator of G Protein Signaling 17 (RGS17)‐induced NSCLC, we showed that miR‐203 was downregulated during tumorigenesis, and inhibited the proliferation and invasion of lung cancer cells. We then determined whether miR‐203 regulated NSCLC by targeting RGS17. To characterize the regulatory effect of miR‐203 on RGS17, we used lung cancer cell lines, A549 and Calu‐1, and the constructed miR‐203 and RGS17 overexpression vectors. The CCK8 kit was used to determine cell proliferation, and the Transwell® assay was used to measure cell invasion and migration. RT‐PCR, western blots, and immunofluorescence were used to analyze expression of miR‐203 and RGS17, and the luciferase reporter assay was used to examine the interaction between miR‐203 and RGS17. Nude mice were used to characterize in vivo tumor growth regulation. Expression of miR‐203 inhibited proliferation, invasion, and migration of lung cancer cell lines A549 and Calu‐1 by targeting RGS17. The regulatory effect of miR‐203 was inhibited after overexpression of RGS17. The luciferase reporter assay showed that miR‐203 downregulated RGS17 by direct integration into the 3′‐UTR of RGS17 mRNA. In vivo studies showed that expression of miR‐203 significantly inhibited growth of tumors. Taken together, the results suggested that expression of miR‐203 inhibited tumor growth and metastasis by targeting RGS17. 相似文献
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17.
Retracted: EphB3‐targeted regulation of miR‐149 in the migration and invasion of human colonic carcinoma HCT116 and SW620 cells
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Guodong Zhang Yinfeng Li Yan Wang Huankun Liang Kangyan Li Laiqing Li Cuicui Chen Wenqiao Sun Shoulei Ren Pengfei Zhu Licheng Zhang 《Cancer science》2017,108(3):408-418
microRNAs play key roles during various crucial cell processes such as proliferation, migration, invasion and apoptosis. Also, microRNAs have been shown to possess oncogenic and tumor‐suppressive functions in human cancers. Here, we describe the regulation and function of miR‐149 in colorectal cancer cell lines. miR‐149 expression patterns were detected in human colorectal cell lines and tissue samples, and then focused on its role in regulation of cell growth, migration, invasion, and its target gene identification. Furthermore, the function of the target gene of miR‐149 was analyzed in vitro and in vivo. miR‐149 expression was downregulated in human colorectal cancer HCT116 and SW620 cell lines compared to the normal colon epithelial NCM460 cell line using quantitative real‐time polymerase chain reaction methods. Further studies indicated that introduction of miR‐149 was able to suppress cell migration and invasion. Then, EphB3 was identified as a direct target gene of miR‐149 in colorectal cancer cells. Moreover, experiments in vitro showed that knockdown expression of EphB3 could suppress cell proliferation and invasion, and ectopic expression of EphB3 restored the phenotypes of CRC cell lines transfected with miR149. In addition, silencing of EphB3 significantly affected cycle progression distribution and increased apoptosis in CRC cell lines. Finally, in vivo results demonstrated that knockdown of EphB3 by siRNA inhibited tumor growth. In conclusion,the important role of miR‐149 in colorectal cancer progression suggesting that miR‐149 may serve as a therapeutic target for colorectal cancer treatment. 相似文献
18.
Erik D. Wiklund Jesper B. Bramsen Toby Hulf Lars Dyrskjøt Ramshanker Ramanathan Thomas B. Hansen Sune B. Villadsen Shan Gao Marie S. Ostenfeld Michael Borre Marcus E. Peter Torben F. Ørntoft Jørgen Kjems Susan J. Clark 《International journal of cancer. Journal international du cancer》2011,128(6):1327-1334
19.
ZFP36L2 promotes cancer cell aggressiveness and is regulated by antitumor microRNA‐375 in pancreatic ductal adenocarcinoma
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Keiichi Yonemori Naohiko Seki Hiroshi Kurahara Yusaku Osako Tetsuya Idichi Takayuki Arai Keiichi Koshizuka Yoshiaki Kita Kosei Maemura Shoji Natsugoe 《Cancer science》2017,108(1):124-135
Due to its aggressive nature, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and hard‐to‐treat malignancies. Recently developed targeted molecular strategies have contributed to remarkable improvements in the treatment of several cancers. However, such therapies have not been applied to PDAC. Therefore, new treatment options are needed for PDAC based on current genomic approaches. Expression of microRNA‐375 (miR‐375) was significantly reduced in miRNA expression signatures of several types of cancers, including PDAC. The aim of the present study was to investigate the functional roles of miR‐375 in PDAC cells and to identify miR‐375‐regulated molecular networks involved in PDAC aggressiveness. The expression levels of miR‐375 were markedly downregulated in PDAC clinical specimens and cell lines (PANC‐1 and SW1990). Ectopic expression of miR‐375 significantly suppressed cancer cell proliferation, migration and invasion. Our in silico and gene expression analyses and luciferase reporter assay showed that zinc finger protein 36 ring finger protein‐like 2 (ZFP36L2) was a direct target of miR‐375 in PDAC cells. Silencing ZFP36L2 inhibited cancer cell aggressiveness in PDAC cell lines, and overexpression of ZFP36L2 was confirmed in PDAC clinical specimens. Interestingly, Kaplan–Meier survival curves showed that high expression of ZFP36L2 predicted shorter survival in patients with PDAC. Moreover, we investigated the downstream molecular networks of the miR‐375/ZFP36L2 axis in PDAC cells. Elucidation of tumor‐suppressive miR‐375‐mediated PDAC molecular networks may provide new insights into the potential mechanisms of PDAC pathogenesis. 相似文献
20.
Wu ZS Wu Q Wang CQ Wang XN Huang J Zhao JJ Mao SS Zhang GH Xu XC Zhang N 《Cancer》2011,117(13):2842-2852