Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

MiR-133b is frequently decreased in gastric cancer and its overexpression reduces the metastatic potential of gastric cancer cells

Authors: Yu Zhao, Jie Huang, Li Zhang, Ying Qu, Jianfang Li, Beiqin Yu, Min Yan, Yingyan Yu, Bingya Liu, Zhenggang Zhu

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

Emerging evidence has shown that microRNAs are involved in gastric cancer development and progression. Here we examine the role of miR-133b in gastric cancer.

Methods

Quantitative real-time PCR analysis was performed in 140 patient gastric cancer tissues and 8 gastric cancer cell lines. The effects of miR-133b in gastric cancer cells metastasis were examined by scratch assay, transwell migration and matrigel invasion. In vivo effects of miR-133b were examined in an intraperitoneal mouse tumor model. Targets of miR-133b were predicted by bioinformatics tools and validated by luciferase reporter analyses, western blot, and quantitative real-time PCR.

Results

MiR-133b was significantly downregulated in 70% (98/140) of gastric cancer patients. Expression of miR-133b was negatively correlated with lymph node metastasis of gastric cancer in patients. Similarly, the expression of miR-133b was significantly lower in seven tested gastric cancer cell lines than in the immortalized non-cancerous GES-1 gastric epithelial cells. Overexpression of miR-133b markedly inhibited metastasis of gastric cancer cells in vitro and in vivo. Moreover, the transcriptional factor Gli1 was identified as a direct target for miR-133b. Level of Gli1 protein but not mRNA was decreased by miR-133b. Activity of luciferase with Gli1 3′-untranslated region was markedly decreased by miR-133b in gastric cancer cells. Gli1 target genes, OPN and Zeb2, were also inhibited by miR133b.

Conclusions

MiR-133b is frequently decreased in gastric cancer. Overexpression of miR-133b inhibits cell metastasis in vitro and in vivo partly by directly suppressing expression of Gli1 protein. These results suggested that miR-133b plays an important role in gastric cancer metastasis.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
Stahlhut Espinosa CE, Slack FJ: The role of microRNAs in cancer. Yale J Biol Med. 2006, 79 (3–4): 131-140.PubMed
3.
Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Canc. 2006, 6 (4): 259-269. 10.1038/nrc1840.CrossRef
4.
Ji Q, Hao XB, Meng Y, Zhang M, DeSano J, Fan DM, Xu L: Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer. 2008, 8: 266-10.1186/1471-2407-8-266.CrossRefPubMedPubMedCentral
5.
Zhang CZ, Han L, Zhang AL, Fu YC, Yue XA, Wang GX, Jia ZF, Pu PY, Zhang QY, Kang CS: MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN. BMC Cancer. 2010, 10: 367-10.1186/1471-2407-10-367.CrossRef
6.
Yu BQ, Su LP, Li JF, Cai Q, Yan M, Chen XH, Yu YY, Gu QL, Zhu ZG, Liu BY: microrna expression signature of gastric cancer cells relative to normal gastric mucosa. Mol Med Rep. 2012, 6 (4): 821-826.PubMed
7.
Feng R, Chen X, Yu Y, Su L, Yu B, Li J, Cai Q, Yan M, Liu B, Zhu Z: miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett. 2010, 298 (1): 50-63. 10.1016/j.canlet.2010.06.004.CrossRefPubMed
8.
Li C, Nie H, Wang M, Su L, Li J, Yu B, Wei M, Ju J, Yu Y, Yan M, et al: MicroRNA-409-3p regulates cell proliferation and apoptosis by targeting PHF10 in gastric cancer. Cancer Lett. 2012, 320 (2): 189-197. 10.1016/j.canlet.2012.02.030.CrossRefPubMed
9.
Wang M, Li C, Nie H, Lv X, Qu Y, Yu B, Su L, Li J, Chen X, Ju J, et al: Down-regulated miR-625 suppresses invasion and metastasis of gastric cancer by targeting ILK. FEBS Lett. 2012, 586 (16): 2382-2388. 10.1016/j.febslet.2012.05.050.CrossRefPubMed
10.
Zhang BG, Li JF, Yu BQ, Zhu ZG, Liu BY, Yan M: microRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN. Oncol Rep. 2012, 27 (4): 1019-1026.PubMedPubMedCentral
11.
Wang M, Li C, Yu B, Su L, Li J, Ju J, Yu Y, Gu Q, Zhu Z, Liu B: Overexpressed miR-301a promotes cell proliferation and invasion by targeting RUNX3 in gastric cancer. J Gastroenterol. 2013, 48 (9): 1023-1033. 10.1007/s00535-012-0733-6.CrossRefPubMed
12.
Li CL, Nie H, Wang M, Su LP, Li JF, Yu YY, Yan M, Qu QL, Zhu ZG, Liu BY: microRNA-155 is downregulated in gastric cancer cells and involved in cell metastasis. Oncol Rep. 2012, 27 (6): 1960-1966.PubMed
13.
Guo J, Miao Y, Xiao B, Huan R, Jiang Z, Meng D, Wang Y: Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol. 2009, 24 (4): 652-657. 10.1111/j.1440-1746.2008.05666.x.CrossRefPubMed
14.
Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang DZ: The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 2006, 38 (2): 228-233. 10.1038/ng1725.CrossRefPubMed
15.
Bandres E, Cubedo E, Agirre X, Malumbres R, Zarate R, Ramirez N, Abajo A, Navarro A, Moreno I, Monzo M, et al: Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006, 5: 29-CrossRefPubMedPubMedCentral
16.
Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI: Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res. 2008, 14 (9): 2588-2592. 10.1158/1078-0432.CCR-07-0666.CrossRefPubMed
17.
Liu X, Chen Z, Yu J, Xia J, Zhou X: MicroRNA profiling and head and neck cancer. Comp Funct Genom. 2009, 2009: 837514-CrossRef
18.
Crawford M, Batte K, Yu L, Wu X, Nuovo GJ, Marsh CB, Otterson GA, Nana-Sinkam SP: MicroRNA 133B targets pro-survival molecules MCL-1 and BCL2L2 in lung cancer. Biochem Biophys Res Commun. 2009, 388 (3): 483-489. 10.1016/j.bbrc.2009.07.143.CrossRefPubMedPubMedCentral
19.
Ichimi T, Enokida H, Okuno Y, Kunimoto R, Chiyomaru T, Kawamoto K, Kawahara K, Toki K, Kawakami K, Nishiyama K, et al: Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer. 2009, 125 (2): 345-352. 10.1002/ijc.24390.CrossRefPubMed
20.
Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, Chiyomaru T, Enokida H, Nakagawa M, Matsubara H: miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 2010, 127 (12): 2804-2814. 10.1002/ijc.25284.CrossRefPubMed
21.
Qin W, Dong P, Ma C, Mitchelson K, Deng T, Zhang L, Sun Y, Feng X, Ding Y, Lu X, et al: MicroRNA-133b is a key promoter of cervical carcinoma development through the activation of the ERK and AKT1 pathways. Oncogene. 2012, 31 (36): 4067-4075. 10.1038/onc.2011.561.CrossRefPubMed
22.
Nohata N, Hanazawa T, Enokida H, Seki N: microRNA-1/133a and microRNA-206/133b clusters: dysregulation and functional roles in human cancers. Oncotarget. 2012, 3 (1): 9-21.PubMedPubMedCentral
23.
Mitas M, Almeida JS, Mikhitarian K, Gillanders WE, Lewin DN, Spyropoulos DD, Hoover L, Graham A, Glenn T, King P, et al: Accurate discrimination of Barrett’s esophagus and esophageal adenocarcinoma using a quantitative three-tiered algorithm and multimarker real-time reverse transcription-PCR. Clin Cancer Res. 2005, 11 (6): 2205-2214. 10.1158/1078-0432.CCR-04-1091.CrossRefPubMed
24.
Lee JL, Wang MJ, Sudhir PR, Chen GD, Chi CW, Chen JY: Osteopontin promotes integrin activation through outside-in and inside-out mechanisms: OPN-CD44V interaction enhances survival in gastrointestinal cancer cells. Cancer Res. 2007, 67 (5): 2089-2097. 10.1158/0008-5472.CAN-06-3625.CrossRefPubMed
25.
Hsu SD, Chu CH, Tsou AP, Chen SJ, Chen HC, Hsu PW, Wong YH, Chen YH, Chen GH, Huang HD: miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes. Nucleic Acids Res. 2008, 36 (Database issue): D165-D169.PubMed
26.
27.
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB: Prediction of mammalian microRNA targets. Cell. 2003, 115 (7): 787-798. 10.1016/S0092-8674(03)01018-3.CrossRefPubMed
28.
29.
Yanai K, Nagai S, Wada J, Yamanaka N, Nakamura M, Torata N, Noshiro H, Tsuneyoshi M, Tanaka M, Katano M: Hedgehog signaling pathway is a possible therapeutic target for gastric cancer. J Surg Oncol. 2007, 95 (1): 55-62. 10.1002/jso.20606.CrossRefPubMed
30.
Yoo YA, Kang MH, Lee HJ, Kim BH, Park JK, Kim HK, Kim JS, Oh SC: Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res. 2011, 71 (22): 7061-7070. 10.1158/0008-5472.CAN-11-1338.CrossRefPubMed
31.
Ohta H, Aoyagi K, Fukaya M, Danjoh I, Ohta A, Isohata N, Saeki N, Taniguchi H, Sakamoto H, Shimoda T: Cross talk between hedgehog and epithelial–mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers. Br J Cancer. 2008, 100 (2): 389-398.CrossRefPubMedPubMedCentral
32.
Dai YH, Tang YP, Zhu HY, Lv L, Chu Y, Zhou YQ, Huo JR: ZEB2 promotes the metastasis of gastric cancer and modulates epithelial mesenchymal transition of gastric cancer cells. Dig Dis Sci. 2012, 57 (5): 1253-1260. 10.1007/s10620-012-2042-6.CrossRefPubMed
33.
Ue T, Yokozaki H, Kitadai Y, Yamamoto S, Yasui W, Ishikawa T, Tahara E: Co‒expression of osteopontin and CD44v9 in gastric cancer. Int J Canc. 1998, 79 (2): 127-132. 10.1002/(SICI)1097-0215(19980417)79:2<127::AID-IJC5>3.0.CO;2-V.CrossRef
34.
Tang X, Li J, Yu B, Su L, Yu Y, Yan M, Liu B, Zhu Z: Osteopontin splice variants differentially exert clinicopathological features and biological functions in gastric cancer. Int J Biol Sci. 2013, 9 (1): 55-66.CrossRefPubMed
35.
Isohata N, Aoyagi K, Mabuchi T, Daiko H, Fukaya M, Ohta H, Ogawa K, Yoshida T, Sasaki H: Hedgehog and epithelial-mesenchymal transition signaling in normal and malignant epithelial cells of the esophagus. Int J Cancer. 2009, 125 (5): 1212-1221. 10.1002/ijc.24400.CrossRefPubMed
36.
Das S, Harris LG, Metge BJ, Liu S, Riker AI, Samant RS, Shevde LA: The hedgehog pathway transcription factor GLI1 promotes malignant behavior of cancer cells by up-regulating osteopontin. J Biol Chem. 2009, 284 (34): 22888-22897. 10.1074/jbc.M109.021949.CrossRefPubMedPubMedCentral
37.
Lim LP, Glasner ME, Yekta S, Burge CB, Bartel DP: Vertebrate microRNA genes. Science. 2003, 299 (5612): 1540-1540. 10.1126/science.1080372.CrossRefPubMed
38.
Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M, et al: A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 2007, 129 (7): 1401-1414. 10.1016/j.cell.2007.04.040.CrossRefPubMedPubMedCentral
39.
Wu WY, Xue XY, Chen ZJ, Han SL, Huang YP, Zhang LF, Zhu GB, Shen X: Potentially predictive microRNAs of gastric cancer with metastasis to lymph node. World J Gastroenterol. 2011, 17 (31): 3645-3651. 10.3748/wjg.v17.i31.3645.CrossRefPubMedPubMedCentral
40.
Cho WC: MicroRNAs in cancer - from research to therapy. Biochim Biophys Acta. 2010, 1805 (2): 209-217.PubMed
41.
Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O’Brien SJ, Wong AJ, Vogelstein B: Identification of an amplified, highly expressed gene in a human glioma. Science. 1987, 236 (4797): 70-73. 10.1126/science.3563490.CrossRefPubMed
42.
Lee J, Platt KA, Censullo P, Ruiz i Altaba A: Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development. 1997, 124 (13): 2537-2552.PubMed
43.
Ji Z, Mei FC, Xie J, Cheng X: Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem. 2007, 282 (19): 14048-14055. 10.1074/jbc.M611089200.CrossRefPubMed
44.
Yoo YA, Kang MH, Kim JS, Oh SC: Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis. 2008, 29 (3): 480-490.CrossRefPubMed
45.
Katoh Y, Katoh M: Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals. Int J Oncol. 2009, 35 (1): 187-192.CrossRefPubMed
46.
Stecca B, Ruiz i Altaba A: A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J. 2009, 28 (6): 663-676. 10.1038/emboj.2009.16.CrossRefPubMedPubMedCentral
47.
Li X, Deng W, Nail CD, Bailey SK, Kraus MH, Ruppert JM, Lobo-Ruppert SM: Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene. 2006, 25 (4): 609-621.PubMedPubMedCentral
48.
Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, et al: Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007, 67 (5): 2187-2196. 10.1158/0008-5472.CAN-06-3281.CrossRefPubMedPubMedCentral
49.
Varnat F, Siegl-Cachedenier I, Malerba M, Gervaz P, Ruiz i Altaba A: Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas. EMBO Mol Med. 2010, 2 (11): 440-457. 10.1002/emmm.201000098.CrossRefPubMedPubMedCentral
50.
Katoh Y, Katoh M: Hedgehog signaling pathway and gastric cancer. Cancer Biol Ther. 2005, 4 (10): 1050-1054. 10.4161/cbt.4.10.2184.CrossRefPubMed
51.
Ma X, Chen K, Huang S, Zhang X, Adegboyega PA, Evers BM, Zhang H, Xie J: Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 2005, 26 (10): 1698-1705. 10.1093/carcin/bgi130.CrossRefPubMed
52.
Ma XL, Sun HI, Wang YS, Huang SH, Xie JW, Zhang HW: Study of Sonic hedgehog signaling pathway related molecules in gastric carcinoma. World J Gastroenterol. 2006, 12 (25): 3965-3969.CrossRefPubMedPubMedCentral
53.
Wen D, Li S, Ji F, Cao H, Jiang W, Zhu J, Fang X: miR-133b acts as a tumor suppressor and negatively regulates FGFR1 in gastric cancer. Tumour Biol. 2013, 34 (2): 793-803. 10.1007/s13277-012-0609-7.CrossRefPubMed
Metadata
Title
MiR-133b is frequently decreased in gastric cancer and its overexpression reduces the metastatic potential of gastric cancer cells
Authors
Yu Zhao
Jie Huang
Li Zhang
Ying Qu
Jianfang Li
Beiqin Yu
Min Yan
Yingyan Yu
Bingya Liu
Zhenggang Zhu
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-34

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

FOXP1inhibits cell growth and attenuates tumorigenicity of neuroblastoma

Research article

Evaluation of superparamagnetic iron oxide-polymer composite microcapsules for magnetic resonance-guided high-intensity focused ultrasound cancer surgery

Case report

Complete pathologic response of HER2-positive breast cancer liver metastasis with dual Anti-HER2 antagonism

Research article

Localization of phosphorylated ErbB1-4 and heregulin in colorectal cancer

Research article

Systemic neutralization of IL-17A significantly reduces breast cancer associated metastasis in arthritic mice by reducing CXCL12/SDF-1 expression in the metastatic niches

Research article

Biomarkers of thyroid function and autoimmunity for predicting high-risk groups of thyroid cancer: a nested case–control study
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits