Skip to main content
Erschienen in: Gastric Cancer 4/2015

01.10.2015 | Original Article

MiR-125b promotes cell migration and invasion by targeting PPP1CA-Rb signal pathways in gastric cancer, resulting in a poor prognosis

verfasst von: Jian-Guo Wu, Jin-Jie Wang, Xin Jiang, Jian-Ping Lan, Xu-Jun He, Hui-Ju Wang, Ying-Yu Ma, Ying-Jie Xia, Guo-Qing Ru, Jie Ma, Zhong-Sheng Zhao, Ren Zhou

Erschienen in: Gastric Cancer | Ausgabe 4/2015

Einloggen, um Zugang zu erhalten

Abstract

Background

MiR-125b functions as an oncogene in many cancers; however, its clinical significance and molecular mechanism in gastric cancers have never been sufficiently investigated. Here, we elucidated the functions and molecular regulated pathways of MiR-125b in gastric cancer.

Methods

We investigated MiR-125b expression in fresh tissues from 50 gastric cancer patients and 6 gastric cancer cell lines using RT-PCR, and explored its prognostic value by hybridizing MiR-125b in situ for 300 clinical gastric tumor tissues with pathological diagnosis and clinical parameters. The effects of MiR-125b on gastric cancer cells and downstream target genes and proteins were analyzed by MTT, transwell assay, RT-PCR, and western blot on the basis of silencing MiR-125b in vitro. Luciferase reporter plasmid was constructed to demonstrate MiR-125b’s direct target.

Results

MiR-125b was upregulated in gastric cancer tissues and cell lines, and significantly promoted cellular proliferation, migration, and invasion by downregulating the expression of PPP1CA and upregulating Rb phosphorylation. MiR-125b expression was significantly correlated with tumor size and depth of invasion, lymph nodes, distant metastasis, and TNM stage. The high-MiR-125b-expression group had a significantly poorer prognosis than the low-expression group (P < 0.05) in stages I, II, and III, and the 5-year survival rate in of the high-expression group was significantly lower than that of the low-expression group.

Conclusions

MiR-125b functions as an oncogene by targeting downregulated PPP1CA and upregulated Rb phosphorylation in gastric cancer. MiR-125b not only promotes cellular proliferation, migration, and invasion in vitro, but also acts as an independent prognostic factor in gastric cancer.
Literatur
1.
Zurück zum Zitat Zhan WH, Han FH. Surgical therapy of gastric cancer in china. J Pract Oncol. 2008;23:91–3. Zhan WH, Han FH. Surgical therapy of gastric cancer in china. J Pract Oncol. 2008;23:91–3.
2.
Zurück zum Zitat Hutvágner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297:2056–60.CrossRefPubMed Hutvágner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297:2056–60.CrossRefPubMed
3.
Zurück zum Zitat Bartels CL, Tsongalis GJ. MicroRNAs: novel biomarkers for human cancer. Clin Chem. 2009;55:623–31.CrossRefPubMed Bartels CL, Tsongalis GJ. MicroRNAs: novel biomarkers for human cancer. Clin Chem. 2009;55:623–31.CrossRefPubMed
4.
5.
Zurück zum Zitat Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci. 2006;103:2257–61.PubMedCentralCrossRefPubMed Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci. 2006;103:2257–61.PubMedCentralCrossRefPubMed
6.
Zurück zum Zitat Iorio MV, Visone R, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699–707.CrossRefPubMed Iorio MV, Visone R, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699–707.CrossRefPubMed
7.
Zurück zum Zitat Nam EJ, Yoon H, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008;14:2690–5.CrossRefPubMed Nam EJ, Yoon H, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008;14:2690–5.CrossRefPubMed
8.
Zurück zum Zitat Bloomston M, Frankel WL, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–8.CrossRefPubMed Bloomston M, Frankel WL, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–8.CrossRefPubMed
9.
Zurück zum Zitat Shi XB, Xue L, et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci. 2007;2007(104):19983–8.CrossRef Shi XB, Xue L, et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci. 2007;2007(104):19983–8.CrossRef
10.
Zurück zum Zitat Bousquet M, Quelen C, Rosati R, et al. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) trans-location. J Exp Med. 2008;205:2499–506.PubMedCentralCrossRefPubMed Bousquet M, Quelen C, Rosati R, et al. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) trans-location. J Exp Med. 2008;205:2499–506.PubMedCentralCrossRefPubMed
11.
Zurück zum Zitat Song LB, Liao WT, Mai HQ, et al. The clinical significance of twist expression in nasopharyngeal carcinoma. Cancer Lett. 2006;242:258–65.CrossRefPubMed Song LB, Liao WT, Mai HQ, et al. The clinical significance of twist expression in nasopharyngeal carcinoma. Cancer Lett. 2006;242:258–65.CrossRefPubMed
12.
Zurück zum Zitat Zhao ZS, Wang YY, Chu YQ, et al. SPARC is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res. 2010;16:260–8.CrossRefPubMed Zhao ZS, Wang YY, Chu YQ, et al. SPARC is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res. 2010;16:260–8.CrossRefPubMed
13.
Zurück zum Zitat Le MT, Xie H, Zhou B, et al. MicroRNA-125b promotes neuronal differentiation in human cells by repressing multiple targets. Mol Cell Biol. 2009;29:5290–305.PubMedCentralCrossRefPubMed Le MT, Xie H, Zhou B, et al. MicroRNA-125b promotes neuronal differentiation in human cells by repressing multiple targets. Mol Cell Biol. 2009;29:5290–305.PubMedCentralCrossRefPubMed
15.
Zurück zum Zitat Lee YS, Kim HK, Chung SM, et al. Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. J Biol Chem. 2005;280:16635–41.CrossRefPubMed Lee YS, Kim HK, Chung SM, et al. Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. J Biol Chem. 2005;280:16635–41.CrossRefPubMed
16.
Zurück zum Zitat Vriens MR, Weng J, Suh I, et al. MicroRNA expression profiling is a potential diagnostic tool for thyroid cancer. Cancer. 2012;118:3426–32.CrossRefPubMed Vriens MR, Weng J, Suh I, et al. MicroRNA expression profiling is a potential diagnostic tool for thyroid cancer. Cancer. 2012;118:3426–32.CrossRefPubMed
17.
Zurück zum Zitat Pallante P, Visone R, Ferracin M, et al. MicroRNA deregulation in human thyroid papillary carcinomas. Endocr Relat Cancer. 2006;13:497–508.CrossRefPubMed Pallante P, Visone R, Ferracin M, et al. MicroRNA deregulation in human thyroid papillary carcinomas. Endocr Relat Cancer. 2006;13:497–508.CrossRefPubMed
18.
Zurück zum Zitat Jia HY, Wang YX, Yan WT, et al. MicroRNA-125b functions as a tumor suppressor in hepatocellular carcinoma cells. Int J Mol Sci. 2012;13:8762–74.PubMedCentralCrossRefPubMed Jia HY, Wang YX, Yan WT, et al. MicroRNA-125b functions as a tumor suppressor in hepatocellular carcinoma cells. Int J Mol Sci. 2012;13:8762–74.PubMedCentralCrossRefPubMed
19.
Zurück zum Zitat Henson BJ, Bhattacharjee S, O’Dee DM, et al. Decreased expression of miR-125b and miR-100 in oral cancer cells contributes to malignancy. Genes Chromosomes Cancer. 2009;48:569–82.PubMedCentralCrossRefPubMed Henson BJ, Bhattacharjee S, O’Dee DM, et al. Decreased expression of miR-125b and miR-100 in oral cancer cells contributes to malignancy. Genes Chromosomes Cancer. 2009;48:569–82.PubMedCentralCrossRefPubMed
20.
Zurück zum Zitat Wang YY, Ye ZY, Zhao ZS, et al. Clinicopathologic significance of miR-10b expression in gastric carcinoma. Human Pathology. 2013;44:1278–85.CrossRefPubMed Wang YY, Ye ZY, Zhao ZS, et al. Clinicopathologic significance of miR-10b expression in gastric carcinoma. Human Pathology. 2013;44:1278–85.CrossRefPubMed
21.
Zurück zum Zitat Wu N, Lin X, Zhao X, et al. MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways. Br J Cancer. 2013;109(11):2853–63.PubMedCentralCrossRefPubMed Wu N, Lin X, Zhao X, et al. MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways. Br J Cancer. 2013;109(11):2853–63.PubMedCentralCrossRefPubMed
22.
Zurück zum Zitat Ferracin M, Bassi C, Pedriali M. miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. Mol Cancer. 2013;12(1):130.PubMedCentralCrossRefPubMed Ferracin M, Bassi C, Pedriali M. miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. Mol Cancer. 2013;12(1):130.PubMedCentralCrossRefPubMed
23.
Zurück zum Zitat Aggen JB, Nairn AC, Chamberlin R. Regulation of protein phosphatase-1. Chem Biol. 2000;7:R13–23.CrossRefPubMed Aggen JB, Nairn AC, Chamberlin R. Regulation of protein phosphatase-1. Chem Biol. 2000;7:R13–23.CrossRefPubMed
24.
Zurück zum Zitat Ceulemans H, Bollen M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev. 2004;84:1–39.CrossRefPubMed Ceulemans H, Bollen M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev. 2004;84:1–39.CrossRefPubMed
25.
Zurück zum Zitat Cohen PT. Protein phosphatase 1–targeted in many directions. J Cell Sci. 2002;115:241–56.PubMed Cohen PT. Protein phosphatase 1–targeted in many directions. J Cell Sci. 2002;115:241–56.PubMed
26.
Zurück zum Zitat Hendrickx A, Beullens M, Ceulemans H, Den Abt T, Van Eynde A, et al. Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol. 2009;16:365–71.CrossRefPubMed Hendrickx A, Beullens M, Ceulemans H, Den Abt T, Van Eynde A, et al. Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol. 2009;16:365–71.CrossRefPubMed
27.
Zurück zum Zitat Ceulemans H, Bollen M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev. 2004;84:1–39.CrossRefPubMed Ceulemans H, Bollen M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev. 2004;84:1–39.CrossRefPubMed
28.
Zurück zum Zitat Berndt N. Protein dephosphorylation and the intracellular control of the cell number. Front Biosci. 1999;4:22–42.CrossRef Berndt N. Protein dephosphorylation and the intracellular control of the cell number. Front Biosci. 1999;4:22–42.CrossRef
29.
Zurück zum Zitat Liu CW, Wang RH, Dohadwala M, et al. Inhibitory phosphorylation of PP1alpha catalytic subunit during the G(1)/S transition. J Biol Chem. 1999;274:29470–5.CrossRefPubMed Liu CW, Wang RH, Dohadwala M, et al. Inhibitory phosphorylation of PP1alpha catalytic subunit during the G(1)/S transition. J Biol Chem. 1999;274:29470–5.CrossRefPubMed
30.
Zurück zum Zitat Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.CrossRefPubMed Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.CrossRefPubMed
32.
Zurück zum Zitat Noonan EJ, Place RF, Basak S, et al. miR-449a causes Rb-dependent cell cycle arrest and senescence in prostate cancer cells. Oncotarget. 2010;1:349–58.PubMedCentralPubMed Noonan EJ, Place RF, Basak S, et al. miR-449a causes Rb-dependent cell cycle arrest and senescence in prostate cancer cells. Oncotarget. 2010;1:349–58.PubMedCentralPubMed
Metadaten
Titel
MiR-125b promotes cell migration and invasion by targeting PPP1CA-Rb signal pathways in gastric cancer, resulting in a poor prognosis
verfasst von
Jian-Guo Wu
Jin-Jie Wang
Xin Jiang
Jian-Ping Lan
Xu-Jun He
Hui-Ju Wang
Ying-Yu Ma
Ying-Jie Xia
Guo-Qing Ru
Jie Ma
Zhong-Sheng Zhao
Ren Zhou
Publikationsdatum
01.10.2015
Verlag
Springer Japan
Erschienen in
Gastric Cancer / Ausgabe 4/2015
Print ISSN: 1436-3291
Elektronische ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-014-0421-8

Weitere Artikel der Ausgabe 4/2015

Gastric Cancer 4/2015 Zur Ausgabe

Update Chirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

S3-Leitlinie „Diagnostik und Therapie des Karpaltunnelsyndroms“

Karpaltunnelsyndrom BDC Leitlinien Webinare
CME: 2 Punkte

Das Karpaltunnelsyndrom ist die häufigste Kompressionsneuropathie peripherer Nerven. Obwohl die Anamnese mit dem nächtlichen Einschlafen der Hand (Brachialgia parästhetica nocturna) sehr typisch ist, ist eine klinisch-neurologische Untersuchung und Elektroneurografie in manchen Fällen auch eine Neurosonografie erforderlich. Im Anfangsstadium sind konservative Maßnahmen (Handgelenksschiene, Ergotherapie) empfehlenswert. Bei nicht Ansprechen der konservativen Therapie oder Auftreten von neurologischen Ausfällen ist eine Dekompression des N. medianus am Karpaltunnel indiziert.

Prof. Dr. med. Gregor Antoniadis
Berufsverband der Deutschen Chirurgie e.V.

S2e-Leitlinie „Distale Radiusfraktur“

Radiusfraktur BDC Leitlinien Webinare
CME: 2 Punkte

Das Webinar beschäftigt sich mit Fragen und Antworten zu Diagnostik und Klassifikation sowie Möglichkeiten des Ausschlusses von Zusatzverletzungen. Die Referenten erläutern, welche Frakturen konservativ behandelt werden können und wie. Das Webinar beantwortet die Frage nach aktuellen operativen Therapiekonzepten: Welcher Zugang, welches Osteosynthesematerial? Auf was muss bei der Nachbehandlung der distalen Radiusfraktur geachtet werden?

PD Dr. med. Oliver Pieske
Dr. med. Benjamin Meyknecht
Berufsverband der Deutschen Chirurgie e.V.

S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“

Appendizitis BDC Leitlinien Webinare
CME: 2 Punkte

Inhalte des Webinars zur S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“ sind die Darstellung des Projektes und des Erstellungswegs zur S1-Leitlinie, die Erläuterung der klinischen Relevanz der Klassifikation EAES 2015, die wissenschaftliche Begründung der wichtigsten Empfehlungen und die Darstellung stadiengerechter Therapieoptionen.

Dr. med. Mihailo Andric
Berufsverband der Deutschen Chirurgie e.V.