Cancer Research Journal
Volume 6, Issue 4, December 2018, Pages: 112-117
Received: Aug. 23, 2018;
Accepted: Sep. 10, 2018;
Published: Oct. 13, 2018
Views 615 Downloads 64
Annada Anil Joshi, Department of Biochemistry, T. N. Medical College & B.Y. L. Nair Ch. Hospital, Mumbai, India
Alka Vishwas Nerurkar, Department of Biochemistry, T. N. Medical College & B.Y. L. Nair Ch. Hospital, Mumbai, India
Neelam Vishwanath Shirsat, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, India
Aberrant expression of the genes involved in Wnt signaling pathway, one of the most important developing pathways, is observed in many malignancies. Reports show that Wnt/β-catenin activation is critical for cancer development, angiogenesis, migration, and invasion. LEF1 belongs to the T cell Factor (TCF)/LEF family of transcription factors and plays the role of nuclear effector in the Wnt/β-catenin signaling pathway. LEF1 has central role as a transcription factor in the Wnt/β-catenin signaling pathway which makes it an ideal target for therapeutic treatment in dealing with cancer proliferation. It can act as an oncogene or a tumor suppressor in cellular context dependent manner. miRNAs are aberrantly expressed in cancers and can act as tumor suppressors or oncomirs depending upon the type of carcinomas. Studies show that miRNAs can be used as novel agents for targeted cancer therapy. miR-106b, which belong to miR-17-92 paralog cluster, is reported to be overexpressed in multiple tumor types including medulloblastomas, breast, colon, kidney, gastric, lung cancer and HCC. In this study we have demonstrated that over-expression of miR-106b-5p down-regulates the endogenous expression of LEF1 in HEK293FT cells, thereby affecting the expression of N-Myc, downstream gene of Wnt signaling. Therefore, our results suggest that miR-106b-5p plays a significant role in suppressing the carcinomas resulted due to the over-expression of LEF1 and/or activation of Wnt pathway and may prove to be a potential target for novel cancer therapy. It may helpful in developing therapeutic strategies for cancer treatments.
Annada Anil Joshi,
Alka Vishwas Nerurkar,
Neelam Vishwanath Shirsat,
Hsa-miR-106b-5p Negatively Regulates LEF1, Cancer Research Journal.
Vol. 6, No. 4,
2018, pp. 112-117.
Clevers H. Wnt/β-catenin signaling in development and disease. Cell. 2006; 127: 469-80.
Wang N, Wang ZY, Wang Y, Xie XM, Shen JG, Peng C, et al. Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation. Oncotarget. 2015; 6: 9854-76.
Kwon OJ, Valdez JM, Zhang L, Zhang B, Wei X, Su Q, et al. Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells. Nat Commun. 2014; 5: 4416
Marchenko GN, Marchenko ND, Leng J, Strongin AY. Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin. Biochem J. 2002; 363: 253-62.
Rathinam R, Berrier A, Alahari SK. Role of Rho GTPases and their regulators in cancer progression. Front Biosci. 2011; 16: 2561-71.
Kangsamaksin T, Murtomaki A, Kofler NM, Cuervo H, Chaudhri RA, Tattersall IW, et al. NOTCH decoys that selectively block DLL/NOTCH or JAG/NOTCH disrupt angiogenesis by unique mechanisms to inhibit tumor growth. Cancer Discov. 2015; 5: 182-97.
Swarup S, Verheyen EM. Wnt/wingless signaling in Drosophila. Cold Spring Harb Perspect Biol 2012; 4 (6): a007930.
Clevers H, Nusse R. Wnt/β‑catenin signaling and disease. Cell 2012; 149 (6): 1192–205.
Kim W, Kim M, Jho EH. Wnt/β‑catenin signalling: from plasma membrane to nucleus. Biochem J 2013; 450 (1): 9–21.
Wang J, Sinha T, Wynshaw‑Boris A. Wnt signaling in mammalian development: lessons from mouse genetics. Cold Spring Harb Perspect Biol 2012; 4 (5): a007963.
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509e1512.
Koleske AJ, Baltimore D, Lisanti MP. Reduction of caveolin and caveolae in oncogenically transformed cells. Proc Natl Acad Sci USA. 1995;280:119e133.
Okamoto T, Schlegel A, Scherer PE, Lisanti MP. Caveolins a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem. 1998;273(10):5419e5422.
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997;16:3797e3804.
Behrens J, Jerchow BA, Wurtele M, et al. Functional interaction of axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998;280:596e599.
Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998;17:1371e1384.
Orford K, Orford CC, Byers SW. Exogenous expression of betacatenin regulates contact inhibition, anchorage-independent growth, and radiation-induced cell cycle arrest. J Cell Biol. 1999;146:855e868.
Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272: 1023e1026.
Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 1996; 10: 1443e1454.
Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005; 434:843e850.
Takebe N, Miele L, Harris PJ, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015; 12:445e464.
Polakis P. Wnt signaling and cancer. Genes Dev. 2000; 14: 1837e1851.
Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science. 2000; 287: 1606e1609.
Morin PJ. Beta-catenin signaling and cancer. Bioessays. 1999; 21:1021e1030.
Petropoulos K, Arseni N, Schessl C, et al. A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med 2008; 205: 515-522.
Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R and Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996; 382: 638-642.
Steinke FC and Xue HH. From inception to output, Tcf1 and Lef1 safeguard development of T-cells and innate immune cells. Immunol Res 2014; 59: 45-55.
Chaw SY, Majeed AA, Dalley AJ, Chan A, Stein S, Farah CS. Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, betacatenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation. Oral Oncol 2012; 48: 997-1006.
Liu LK, Jiang XY, Zhou XX, Wang DM, Song XL, Jiang HB. Upregulation of vimentin and aberrant expression of E-cadherin/beta-catenin complex in oral squamous cell carcinomas: correlation with the clinicopathological features and patient outcome. Mod Pathol 2010; 23: 213-224.
Su MC, Chen CT, Huang FI, Chen YL, Jeng YM, Lin CY. Expression of LEF1 is an independent prognostic factor for patients with oral squamous cell carcinoma. J Formos Med Assoc 2014; 113: 934-939.
Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115: 3206-3214.
Tandon B, Peterson L, Gao J, Nelson B, Ma S, Rosen S, Chen YH. Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas. Mod Pathol 2011; 24: 1433-1443.
Menter T, Dirnhofer S, Tzankov A. LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol 2015; 68: 473-478.
Wu W, Zhu H, Fu Y, Shen W, et la. High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid. Oncotarget 2016; 7: 21631-43.
Walther N, Ulrich A, Vockerodt M, et al. Aberrant lymphocyte enhancer-binding factor 1 expression is characteristic for sporadic Burkitt’s lymphoma. Am J Pathol 2013; 182: 1092-1098.
Wang WJ, Yao Y, Jiang LL, et al. Knockdown of lymphoid enhancer factor 1 inhibits colon cancer progression in vitro and in vivo. PLoS One 2013; 8: e76596.
Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 1997; 57: 314-319.
Shang D, Liu Y, Xu X, Han T, Tian Y. 5-aza-2’-deoxycytidine enhances susceptibility of renal cell carcinoma to paclitaxel by decreasing LEF1/phospho-β-catenin expression. Cancer Lett 2011; 311: 230-236.
Dräger J, Keller KS, et al. LEF1 reduces tumor progression and induces myodifferentiation in a subset of rhabdomyosarcoma. Oncotarget. 2017, 8(2): 3259–3273.
Staal FJT, Clevers H. Tales of the Unexpected: Tcf1 Functions as a Tumor Suppressor for Leukemias. Cell, 2012, 37 (5): 761-763.
Gutierrez A, Sanda T, et al.LEF1 Is a Tumor Suppressor in T Cell Acute Lymphoblastic Leukemia. Blood 2015, 112 (11): 3802.
Bartel,D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297.
Bartel,D.P. MicroRNAs: target recognition and regulatory functions. Cell 2009, 136, 215–233.
Croce,C.M. Causes and consequences of microRNA dysregulation in cancer. Nat. Rev. Genet. 2009, 10, 704–714.
Gokhale A., Kunder R., et al. Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway. Journal of Cancer Research and Therapeutics 2010, 6 (4), 521-529.
Li,Y. et al. Role of the miR-106b-25 microRNA cluster in hepatocellular carcinoma. Cancer Sci. 2009, 100, 1234–1242.
Li,B. et al. Down-regulation of microRNA 106b is involved in p21- mediated cell cycle arrest in response to radiation in prostate cancer cells. Prostate 2011, 71, 567–574.
Tsujiura,M. et al. Circulating microRNAs in plasma of patients with gastric cancers. Br. J. Cancer 2010, 102, 1174–1179.
Shen G, Jia H, Tai Q, Li Y, Chen D. miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis 2013, 34, 211–219.