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Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary research

MiR-144-3p promotes the tumor growth and metastasis of papillary thyroid carcinoma by targeting paired box gene 8

Authors: Chang Liu, Chang Su, Yanchun Chen, Guang Li

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

Paired box gene 8 (PAX8) is expressed in and indispensable to thyroid development. MiR-144-3p is found dys-regulated in cancers, and it can block the expression of target gens. This study sought to understand the effect of MiR-144-3p in papillary thyroid carcinoma (PTC) as well as the associated mechanisms.

Materials and methods

Real-time PCR, immunohistochemical and Western blot assays were performed to examine the expression of target miRNA and/or genes. CCK-8 and flow cytometry analysis was used to respectively test cell growth, cell cycle progression and apoptosis. Luciferase reporter assay was performed to find out whether miR-144-3p could bind to the 3′ untranslated region of PAX8 or not.

Results

We found that PAX8 decreased in PTC, while miR-144-3p increased in PTC. Over-expression of miR-144-3p promoted the cell viability and cell cycle progression. The expressions of cell-cycle-related genes, cyclin D1, cyclin-dependent kinase 2 and CDC25A were modulated by miR-144-3p. Meanwhile, the presence or absence of miR-144-3p both affected epithelial-mesenchymal transition of PTC by regulating the expression of E-cadherin, N-cadherin and vimentin. Moreover, PAX8 may be a potential direct target of miR-144-3p. Mechanically, the activation of extracellular signal–regulated kinases 1/2, Akt and c-Jun N-terminal kinases may be associated with the tumor-promoting effect of miR-144-3p. In addition, the blockage of miR-144-3p forced the anti-tumor effect delivered by X-ray exposure or paclitaxel.

Conclusion

MiR-144-3p promoted the growth of tumor and the metastasis of PTC by targeting PAX 8. The study provided promising prognosis markers and valuable treatment strategy for PTC.
Literature
2.
go back to reference Dinets A, Hulchiy M, Sofiadis A, Ghaderi M, Hoog A, Larsson C, Zedenius J. Clinical, genetic, and immunohistochemical characterization of 70 Ukrainian adult cases with post-Chornobyl papillary thyroid carcinoma. Eur J Endocrinol. 2012;166(6):1049–60.CrossRefPubMedPubMedCentral Dinets A, Hulchiy M, Sofiadis A, Ghaderi M, Hoog A, Larsson C, Zedenius J. Clinical, genetic, and immunohistochemical characterization of 70 Ukrainian adult cases with post-Chornobyl papillary thyroid carcinoma. Eur J Endocrinol. 2012;166(6):1049–60.CrossRefPubMedPubMedCentral
3.
go back to reference Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev. 2007;28(7):742–62.CrossRefPubMed Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev. 2007;28(7):742–62.CrossRefPubMed
4.
go back to reference Walther C, Guenet JL, Simon D, Deutsch U, Jostes B, Goulding MD, Plachov D, Balling R, Gruss P. Pax: a murine multigene family of paired box-containing genes. Genomics. 1991;11(2):424–34.CrossRefPubMed Walther C, Guenet JL, Simon D, Deutsch U, Jostes B, Goulding MD, Plachov D, Balling R, Gruss P. Pax: a murine multigene family of paired box-containing genes. Genomics. 1991;11(2):424–34.CrossRefPubMed
5.
go back to reference Nonaka D, Tang Y, Chiriboga L, Rivera M, Ghossein R. Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol. 2008;21(2):192–200.CrossRefPubMed Nonaka D, Tang Y, Chiriboga L, Rivera M, Ghossein R. Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol. 2008;21(2):192–200.CrossRefPubMed
6.
go back to reference Lacroix L, Mian C, Barrier T, Talbot M, Caillou B, Schlumberger M, Bidart JM. PAX8 and peroxisome proliferator-activated receptor gamma 1 gene expression status in benign and malignant thyroid tissues. Eur J Endocrinol. 2004;151(3):367–74.CrossRefPubMed Lacroix L, Mian C, Barrier T, Talbot M, Caillou B, Schlumberger M, Bidart JM. PAX8 and peroxisome proliferator-activated receptor gamma 1 gene expression status in benign and malignant thyroid tissues. Eur J Endocrinol. 2004;151(3):367–74.CrossRefPubMed
7.
go back to reference Arturi F, Russo D, Bidart JM, Scarpelli D, Schlumberger M, Filetti S. Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors. Eur J Endocrinol. 2001;145(2):129–35.CrossRefPubMed Arturi F, Russo D, Bidart JM, Scarpelli D, Schlumberger M, Filetti S. Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors. Eur J Endocrinol. 2001;145(2):129–35.CrossRefPubMed
8.
go back to reference Ros P, Rossi DL, Acebron A, Santisteban P. Thyroid-specific gene expression in the multi-step process of thyroid carcinogenesis. Biochimie. 1999;81(4):389–96.CrossRefPubMed Ros P, Rossi DL, Acebron A, Santisteban P. Thyroid-specific gene expression in the multi-step process of thyroid carcinogenesis. Biochimie. 1999;81(4):389–96.CrossRefPubMed
11.
12.
13.
go back to reference Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005;353(17):1793–801.CrossRefPubMed Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005;353(17):1793–801.CrossRefPubMed
14.
go back to reference Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69.CrossRefPubMed Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69.CrossRefPubMed
15.
go back to reference Boufraqech M, Zhang L, Jain M, Patel D, Ellis R, Xiong Y, He M, Nilubol N, Merino MJ, Kebebew E. miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocr Relat Cancer. 2014;21(4):517–31.CrossRefPubMed Boufraqech M, Zhang L, Jain M, Patel D, Ellis R, Xiong Y, He M, Nilubol N, Merino MJ, Kebebew E. miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocr Relat Cancer. 2014;21(4):517–31.CrossRefPubMed
16.
go back to reference Carvalheira G, Nozima BH, Cerutti JM. microRNA-106b-mediated down-regulation of C1orf24 expression induces apoptosis and suppresses invasion of thyroid cancer. Oncotarget. 2015;6(29):28357–70.CrossRefPubMedPubMedCentral Carvalheira G, Nozima BH, Cerutti JM. microRNA-106b-mediated down-regulation of C1orf24 expression induces apoptosis and suppresses invasion of thyroid cancer. Oncotarget. 2015;6(29):28357–70.CrossRefPubMedPubMedCentral
17.
go back to reference Iwaya T, Yokobori T, Nishida N, Kogo R, Sudo T, Tanaka F, Shibata K, Sawada G, Takahashi Y, Ishibashi M, et al. Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. Carcinogenesis. 2012;33(12):2391–7.CrossRefPubMed Iwaya T, Yokobori T, Nishida N, Kogo R, Sudo T, Tanaka F, Shibata K, Sawada G, Takahashi Y, Ishibashi M, et al. Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. Carcinogenesis. 2012;33(12):2391–7.CrossRefPubMed
18.
19.
go back to reference Namlos HM, Meza-Zepeda LA, Baroy T, Ostensen IH, Kresse SH, Kuijjer ML, Serra M, Burger H, Cleton-Jansen AM, Myklebost O. Modulation of the osteosarcoma expression phenotype by microRNAs. PLoS ONE. 2012;7(10):25.CrossRef Namlos HM, Meza-Zepeda LA, Baroy T, Ostensen IH, Kresse SH, Kuijjer ML, Serra M, Burger H, Cleton-Jansen AM, Myklebost O. Modulation of the osteosarcoma expression phenotype by microRNAs. PLoS ONE. 2012;7(10):25.CrossRef
20.
go back to reference Katayama Y, Maeda M, Miyaguchi K, Nemoto S, Yasen M, Tanaka S, Mizushima H, Fukuoka Y, Arii S, Tanaka H. Identification of pathogenesis-related microRNAs in hepatocellular carcinoma by expression profiling. Oncol Lett. 2012;4(4):817–23.CrossRefPubMedPubMedCentral Katayama Y, Maeda M, Miyaguchi K, Nemoto S, Yasen M, Tanaka S, Mizushima H, Fukuoka Y, Arii S, Tanaka H. Identification of pathogenesis-related microRNAs in hepatocellular carcinoma by expression profiling. Oncol Lett. 2012;4(4):817–23.CrossRefPubMedPubMedCentral
21.
go back to reference Kanteti R, El-Hashani E, Dhanasingh I, Tretiakova M, Husain AN, Sharma S, Sharma J, Vokes EE, Salgia R. Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer. BMC Cancer. 2014;14:185.CrossRefPubMedPubMedCentral Kanteti R, El-Hashani E, Dhanasingh I, Tretiakova M, Husain AN, Sharma S, Sharma J, Vokes EE, Salgia R. Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer. BMC Cancer. 2014;14:185.CrossRefPubMedPubMedCentral
22.
go back to reference Diao WL, Luo L, Luo Q. Effect of X-ray irradiation on epithelial-mesenchymal transition of colorectal cancer SW480 cells. J Biol Regul Homeost Agents. 2016;30(2):553–8.PubMed Diao WL, Luo L, Luo Q. Effect of X-ray irradiation on epithelial-mesenchymal transition of colorectal cancer SW480 cells. J Biol Regul Homeost Agents. 2016;30(2):553–8.PubMed
23.
go back to reference Li R, Moudgil T, Ross HJ, Hu HM. Apoptosis of non-small-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim. Cell Death Differ. 2005;12(3):292–303.CrossRefPubMed Li R, Moudgil T, Ross HJ, Hu HM. Apoptosis of non-small-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim. Cell Death Differ. 2005;12(3):292–303.CrossRefPubMed
24.
go back to reference Arocho A, Chen B, Ladanyi M, Pan Q. Validation of the 2− ΔΔCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts. Diagn Mol Pathol. 2006;15(1):56–61.CrossRefPubMed Arocho A, Chen B, Ladanyi M, Pan Q. Validation of the 2− ΔΔCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts. Diagn Mol Pathol. 2006;15(1):56–61.CrossRefPubMed
25.
go back to reference Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411(6835):342–8.CrossRefPubMed Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411(6835):342–8.CrossRefPubMed
26.
go back to reference Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E. Epithelial-mesenchymal transition. Cancer Res. 2008;68(23):9574–7.CrossRefPubMed Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E. Epithelial-mesenchymal transition. Cancer Res. 2008;68(23):9574–7.CrossRefPubMed
27.
go back to reference Nga ME, Lim GS, Soh CH, Kumarasinghe MP. HBME-1 and CK19 are highly discriminatory in the cytological diagnosis of papillary thyroid carcinoma. Diagn Cytopathol. 2008;36(8):550–6.CrossRefPubMed Nga ME, Lim GS, Soh CH, Kumarasinghe MP. HBME-1 and CK19 are highly discriminatory in the cytological diagnosis of papillary thyroid carcinoma. Diagn Cytopathol. 2008;36(8):550–6.CrossRefPubMed
28.
go back to reference Sharma R, Sanchez-Ferras O, Bouchard M. Pax genes in renal development, disease and regeneration. Semin Cell Dev Biol. 2015;44:97–106.CrossRefPubMed Sharma R, Sanchez-Ferras O, Bouchard M. Pax genes in renal development, disease and regeneration. Semin Cell Dev Biol. 2015;44:97–106.CrossRefPubMed
29.
go back to reference Puglisi F, Cesselli D, Damante G, Pellizzari L, Beltrami CA, Di Loreto C. Expression of Pax-8, p53 and bcl-2 in human benign and malignant thyroid diseases. Anticancer Res. 2000;20(1A):311–6.PubMed Puglisi F, Cesselli D, Damante G, Pellizzari L, Beltrami CA, Di Loreto C. Expression of Pax-8, p53 and bcl-2 in human benign and malignant thyroid diseases. Anticancer Res. 2000;20(1A):311–6.PubMed
30.
go back to reference Rosignolo F, Sponziello M, Durante C, Puppin C, Mio C, Baldan F, Di Loreto C, Russo D, Filetti S, Damante G. Expression of PAX8 target genes in papillary thyroid carcinoma. PLoS ONE. 2016;11(6):e0156658.CrossRefPubMedPubMedCentral Rosignolo F, Sponziello M, Durante C, Puppin C, Mio C, Baldan F, Di Loreto C, Russo D, Filetti S, Damante G. Expression of PAX8 target genes in papillary thyroid carcinoma. PLoS ONE. 2016;11(6):e0156658.CrossRefPubMedPubMedCentral
32.
go back to reference Lou N, Ruan AM, Qiu B, Bao L, Xu YC, Zhao Y, Sun RL, Zhang ST, Xu GH, Ruan HL, et al. miR-144-3p as a novel plasma diagnostic biomarker for clear cell renal cell carcinoma. Urol Oncol. 2017;35(1):12.CrossRef Lou N, Ruan AM, Qiu B, Bao L, Xu YC, Zhao Y, Sun RL, Zhang ST, Xu GH, Ruan HL, et al. miR-144-3p as a novel plasma diagnostic biomarker for clear cell renal cell carcinoma. Urol Oncol. 2017;35(1):12.CrossRef
33.
go back to reference Flemington EK, Speck SH, Kaelin WG Jr. E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci USA. 1993;90(15):6914–8.CrossRefPubMedPubMedCentral Flemington EK, Speck SH, Kaelin WG Jr. E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci USA. 1993;90(15):6914–8.CrossRefPubMedPubMedCentral
35.
go back to reference Du R, Wu S, Lv X, Fang H, Wu S, Kang J. Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. J Exp Clin Cancer Res. 2014;33(1):105.CrossRefPubMedPubMedCentral Du R, Wu S, Lv X, Fang H, Wu S, Kang J. Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. J Exp Clin Cancer Res. 2014;33(1):105.CrossRefPubMedPubMedCentral
37.
go back to reference Pan H-L, Wen Z-S, Huang Y-C, Cheng X, Wang G-Z, Zhou Y-C, Wang Z-Y, Guo Y-Q, Cao Y, Zhou G-B. Down-regulation of microRNA-144 in air pollution-related lung cancer. Sci Rep. 2015;5:14331.CrossRefPubMedPubMedCentral Pan H-L, Wen Z-S, Huang Y-C, Cheng X, Wang G-Z, Zhou Y-C, Wang Z-Y, Guo Y-Q, Cao Y, Zhou G-B. Down-regulation of microRNA-144 in air pollution-related lung cancer. Sci Rep. 2015;5:14331.CrossRefPubMedPubMedCentral
38.
go back to reference Zhang SY, Lu ZM, Lin YF, Chen LS, Luo XN, Song XH, Chen SH, Wu YL. miR-144-3p, a tumor suppressive microRNA targeting ETS-1 in laryngeal squamous cell carcinoma. Oncotarget. 2016;7(10):11637–50.PubMedPubMedCentral Zhang SY, Lu ZM, Lin YF, Chen LS, Luo XN, Song XH, Chen SH, Wu YL. miR-144-3p, a tumor suppressive microRNA targeting ETS-1 in laryngeal squamous cell carcinoma. Oncotarget. 2016;7(10):11637–50.PubMedPubMedCentral
39.
go back to reference Lan F, Yu H, Hu M, Xia T, Yue X. miR-144-3p exerts anti-tumor effects in glioblastoma by targeting c-Met. J Neurochem. 2015;135(2):274–86.CrossRefPubMed Lan F, Yu H, Hu M, Xia T, Yue X. miR-144-3p exerts anti-tumor effects in glioblastoma by targeting c-Met. J Neurochem. 2015;135(2):274–86.CrossRefPubMed
40.
go back to reference Yacoub A, Gupta P, Park MA, Rhamani M, Hamed H, Hanna D, Zhang G, Sarkar D, Lebedeva IV, Emdad L, et al. Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. Mol Cancer Ther. 2008;7(2):314–29.CrossRefPubMed Yacoub A, Gupta P, Park MA, Rhamani M, Hamed H, Hanna D, Zhang G, Sarkar D, Lebedeva IV, Emdad L, et al. Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. Mol Cancer Ther. 2008;7(2):314–29.CrossRefPubMed
41.
go back to reference Brand S, Olszak T, Beigel F, Diebold J, Otte J-M, Eichhorst ST, Göke B, Dambacher J. Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells. J Cell Biochem. 2006;97(4):709–23.CrossRefPubMed Brand S, Olszak T, Beigel F, Diebold J, Otte J-M, Eichhorst ST, Göke B, Dambacher J. Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells. J Cell Biochem. 2006;97(4):709–23.CrossRefPubMed
42.
go back to reference Caron RW, Yacoub A, Mitchell C, Zhu X, Hong Y, Sasazuki T, Shirasawa S, Hagan MP, Grant S, Dent P. Radiation-stimulated ERK1/2 and JNK1/2 signaling can promote cell cycle progression in human colon cancer cells. Cell Cycle. 2005;4(3):456–64.CrossRefPubMed Caron RW, Yacoub A, Mitchell C, Zhu X, Hong Y, Sasazuki T, Shirasawa S, Hagan MP, Grant S, Dent P. Radiation-stimulated ERK1/2 and JNK1/2 signaling can promote cell cycle progression in human colon cancer cells. Cell Cycle. 2005;4(3):456–64.CrossRefPubMed
43.
go back to reference Uzgare AR, Kaplan PJ, Greenberg NM. Differential expression and/or activation of P38MAPK, erk1/2, and jnk during the initiation and progression of prostate cancer. Prostate. 2003;55(2):128–39.CrossRefPubMed Uzgare AR, Kaplan PJ, Greenberg NM. Differential expression and/or activation of P38MAPK, erk1/2, and jnk during the initiation and progression of prostate cancer. Prostate. 2003;55(2):128–39.CrossRefPubMed
44.
go back to reference Chen JH, Lin SS, Wang WX, Yuan ST, Shi JS, Jia AQ. The extract, LXB-1, from the barks of Liriodendron× hybrid, induced apoptosis via Akt, JNK and ERK1/2 pathways in A549 lung cancer cells. Z Naturforsch C. 2015;70(11–12):305–11.PubMed Chen JH, Lin SS, Wang WX, Yuan ST, Shi JS, Jia AQ. The extract, LXB-1, from the barks of Liriodendron× hybrid, induced apoptosis via Akt, JNK and ERK1/2 pathways in A549 lung cancer cells. Z Naturforsch C. 2015;70(11–12):305–11.PubMed
45.
go back to reference Nasu Y, Benke A, Arakawa S, Yoshida GJ, Kawamura G, Manley S, Shimizu S, Ozawa T. In situ characterization of bak clusters responsible for cell death using single molecule localization microscopy. Sci Rep. 2016;6:27505.CrossRefPubMedPubMedCentral Nasu Y, Benke A, Arakawa S, Yoshida GJ, Kawamura G, Manley S, Shimizu S, Ozawa T. In situ characterization of bak clusters responsible for cell death using single molecule localization microscopy. Sci Rep. 2016;6:27505.CrossRefPubMedPubMedCentral
46.
go back to reference Muhammad EM, Ahmad AN, Guirguis MN, Ali AEM. Evaluation of immunohistochemical anti-apoptotic Bcl-2 and pro-apoptotic Bax gene products in breast carcinoma. Egypt J Med Sci. 2009;30(2):1199–227. Muhammad EM, Ahmad AN, Guirguis MN, Ali AEM. Evaluation of immunohistochemical anti-apoptotic Bcl-2 and pro-apoptotic Bax gene products in breast carcinoma. Egypt J Med Sci. 2009;30(2):1199–227.
Metadata
Title
MiR-144-3p promotes the tumor growth and metastasis of papillary thyroid carcinoma by targeting paired box gene 8
Authors
Chang Liu
Chang Su
Yanchun Chen
Guang Li
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0550-y

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