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

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

TFAP2C promotes stemness and chemotherapeutic resistance in colorectal cancer via inactivating hippo signaling pathway

Authors: Xu Wang, Di Sun, Jiandong Tai, Si Chen, Miao Yu, Dong Ren, Lei Wang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Aberrant expression of transcription Factor AP-2 Gamma (TFAP2C) has been reported to be implicated in malignant process of many cancers. The purpose of this study is to investigate the clinical significance and biological roles of TFAP2C in colorectal cancer (CRC).

Methods

TFAP2C expression was evaluated by real-time PCR, Western blot and immunohistochemistry (IHC) respectively in clinical CRC tissues. Statistical analysis was performed to explore the correlation between TFAP2C expression and clinicopathological features, and overall and progression-free survival in CRC patients. In vitro and in vivo assays were performed to assess the biological roles of TFAP2C in CRC cells. Western blot, luciferase and Chromatin immunoprecipitation (ChIP) assays were used to identify the underlying pathway mediating the biological roles of TFAP2C in CRC.

Results

TFAP2C is robustly upregulated in CRC tissues and cells, and high expression of TFAP2C correlates with advanced clinicopathological features, poor prognosis and disease progression in CRC patients. Furthermore, upregulating TFAP2C enhances spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and reduces the apoptosis induced by 5-fluorouracil in colorectal cancer cells in vitro, and promotes stemness and chemoresistance of CRC cells in vivo; while silencing TFAP2C yields an opposite effect. Importantly, downregulation of TFAP2C dramatically restores chemotherapeutic sensitivity of CRC cells to 5-FU in vivo. Our results further demonstrate that TFAP2C promotes stemness and chemoresistance of CRC cells to 5-FU by inhibiting Hippo signaling via transcriptionally upregulating ROCK1 and ROCK2 in CRC cells.

Conclusion

Our findings indicate that TFAP2C may serve as a novel prognostic factor in CRC patients, and a therapeutic target for the treatment of CRC, suggesting that silencing TFAP2C in combination with 5-FU may be an effective therapeutic strategy to improve survival in CRC patients.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225–49.CrossRefPubMed
2.
Ricci-Vitiani L, Fabrizi E, Palio E, De Maria R. Colon Cancer stem cells. J Mol Med. 2009;87(11):1097–104.CrossRefPubMed
3.
Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J clin oncol. 2000;18(1):136–47.CrossRefPubMed
4.
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041–7.CrossRefPubMed
5.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.CrossRefPubMed
6.
Park EK, Lee JC, Park JW, Bang SY, Yi SA, Kim BK, Park JH, Kwon SH, You JS, Nam SW, et al. Transcriptional repression of cancer stem cell marker CD133 by tumor suppressor p53. Cell Death Dis. 2015;6:e1964.CrossRefPubMedPubMedCentral
7.
8.
Ge G, Zhou C, Ren Y, Tang X, Wang K, Zhang W, Niu L, Zhou Y, Yan Y, He J. Enhanced SLC34A2 in breast cancer stem cell-like cells induces chemotherapeutic resistance to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling. Tumour biol. 2016;37(4):5049–62.CrossRefPubMed
9.
Zhang L, Sun H, Zhao F, Lu P, Ge C, Li H, Hou H, Yan M, Chen T, Jiang G, et al. BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma. Cancer Res. 2012;72(16):4276–85.CrossRefPubMed
10.
11.
Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ. Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature. 1996;381(6579):235–8.CrossRefPubMed
12.
Zhang J, Hagopian-Donaldson S, Serbedzija G, Elsemore J, Plehn-Dujowich D, AP MM, Flavell RA, Williams T. Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature. 1996;381(6579):238–41.CrossRefPubMed
13.
Shi D, Xiao X, Tian Y, Qin L, Xie F, Sun R, Wang J, Li W, Liu T, Xiao Y, et al. Activating enhancer-binding protein-2alpha induces cyclooxygenase-2 expression and promotes nasopharyngeal carcinoma growth. Oncotarget. 2015;6(7):5005–21.PubMed
14.
Fu L, Shi K, Wang J, Chen W, Shi D, Tian Y, Guo W, Yu W, Xiao X, Kang T, et al. TFAP2B overexpression contributes to tumor growth and a poor prognosis of human lung adenocarcinoma through modulation of ERK and VEGF/PEDF signaling. Mol Cancer. 2014;13:89.CrossRefPubMedPubMedCentral
15.
Berlato C, Chan KV, Price AM, Canosa M, Scibetta AG, Hurst HC. Alternative TFAP2A isoforms have distinct activities in breast cancer. Breast cancer res. 2011;13(2):R23.CrossRefPubMed
16.
De Andrade JP, Park JM, Gu VW, Woodfield GW, Kulak MV, Lorenzen AW, Wu VT, Van Dorin SE, Spanheimer PM, Weigel RJ. EGFR is regulated by TFAP2C in luminal breast cancer and is a target for Vandetanib. Mol Cancer Ther. 2016;15(3):503–11.CrossRefPubMedPubMedCentral
17.
Ebert MP, Tanzer M, Balluff B, Burgermeister E, Kretzschmar AK, Hughes DJ, Tetzner R, Lofton-Day C, Rosenberg R, Reinacher-Schick AC, et al. TFAP2E-DKK4 and chemoresistance in colorectal cancer. N Engl J Med. 2012;366(1):44–53.CrossRefPubMed
18.
19.
20.
Harvey KF, Zhang X, Thomas DM. The hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246–57.CrossRefPubMed
21.
Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008;28(7):2426–36.CrossRefPubMedPubMedCentral
22.
Oka T, Mazack V, Sudol M: Mst2 and Lats kinases regulate apoptotic function of yes kinase-associated protein (YAP). J Biol Chem 2008, 283(41):27534-27546.
23.
Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem. 2009;284(20):13355–62.CrossRefPubMedPubMedCentral
24.
Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, Wang Y, Halder G, Finegold MJ, Lee JS, et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci U S A. 2010;107(4):1437–42.CrossRefPubMedPubMedCentral
25.
Imajo M, Miyatake K, Iimura A, Miyamoto A, Nishida E. A molecular mechanism that links hippo signalling to the inhibition of Wnt/beta-catenin signalling. EMBO J. 2012;31(5):1109–22.CrossRefPubMedPubMedCentral
26.
Chen M, Wang M, Xu S, Guo X, Jiang J. Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the hippo signaling pathway. Oncotarget. 2015;6(42):44466–79.CrossRefPubMedPubMedCentral
27.
Touil Y, Igoudjil W, Corvaisier M, Dessein AF, Vandomme J, Monte D, Stechly L, Skrypek N, Langlois C, Grard G, et al. Colon Cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-yes/YAP axis. Clin cancer res. 2014;20(4):837–46.CrossRefPubMed
28.
Ren D, Yang Q, Dai Y, Guo W, Du H, Song L, Peng X. Oncogenic miR-210-3p promotes prostate cancer cell EMT and bone metastasis via NF-kappaB signaling pathway. Mol Cancer. 2017;16(1):117.CrossRefPubMedPubMedCentral
29.
30.
Ren D, Wang M, Guo W, Zhao X, Tu X, Huang S, Zou X, Peng X. Wild-type p53 suppresses the epithelial-mesenchymal transition and stemness in PC-3 prostate cancer cells by modulating miR145. Int J Oncol. 2013;42(4):1473–81.CrossRefPubMed
31.
Zhang X, Ren D, Guo L, Wang L, Wu S, Lin C, Ye L, Zhu J, Li J, Song L, et al. Thymosin beta 10 is a key regulator of tumorigenesis and metastasis and a novel serum marker in breast cancer. Breast cancer res. 2017;19(1):15.CrossRefPubMedPubMedCentral
32.
33.
Wang M, Ren D, Guo W, Huang S, Wang Z, Li Q, Du H, Song L, Peng X. N-cadherin promotes epithelial-mesenchymal transition and cancer stem cell-like traits via ErbB signaling in prostate cancer cells. Int J Oncol. 2016;48(2):595–606.CrossRefPubMed
34.
Ren D, Lin B, Zhang X, Peng Y, Ye Z, Ma Y, Liang Y, Cao L, Li X, Li R, et al. Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway. Oncotarget. 2017;8(30):49807–49823.https://​doi.​org/​10.​18632/​oncotarget.​17971. PMID: 28591704.
35.
36.
Ren D, Wang M, Guo W, Huang S, Wang Z, Zhao X, Du H, Song L, Peng X. Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells. Cell Tissue Res. 2014;358(3):763–78.CrossRefPubMed
37.
Guo W, Ren D, Chen X, Tu X, Huang S, Wang M, Song L, Zou X, Peng X. HEF1 promotes epithelial mesenchymal transition and bone invasion in prostate cancer under the regulation of microRNA-145. J Cell Biochem. 2013;114(7):1606–15.CrossRefPubMed
38.
Zhang X, Zhang L, Lin B, Chai X, Li R, Liao Y, Deng X, Liu Q, Yang W, Cai Y, et al. Phospholipid Phosphatase 4 promotes proliferation and tumorigenesis, and activates Ca2+−permeable Cationic Channel in lung carcinoma cells. Mol Cancer. 2017;16(1):147.CrossRefPubMedPubMedCentral
39.
Kono K, Tamashiro DA, Alarcon VB. Inhibition of RHO-ROCK signaling enhances ICM and suppresses TE characteristics through activation of hippo signaling in the mouse blastocyst. Dev Biol. 2014;394(1):142–55.CrossRefPubMedPubMedCentral
40.
Kang J, Kim W, Lee S, Kwon D, Chun J, Son B, Kim E, Lee JM, Youn H, Youn B. TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation. Oncogene. 2017;36(11):1585–96.CrossRefPubMed
41.
Ikram F, Ackermann S, Kahlert Y, Volland R, Roels F, Engesser A, Hertwig F, Kocak H, Hero B, Dreidax D, et al. Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma. Mol Oncol. 2016;10(2):344–59.CrossRefPubMed
42.
Pellikainen JM, Kosma VM. Activator protein-2 in carcinogenesis with a special reference to breast cancer--a mini review. Int J Cancer. 2007;120(10):2061–7.CrossRefPubMed
43.
Williams CM, Scibetta AG, Friedrich JK, Canosa M, Berlato C, Moss CH, Hurst HC. AP-2gamma promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene. EMBO J. 2009;28(22):3591–601.CrossRefPubMedPubMedCentral
44.
Gee JM, Eloranta JJ, Ibbitt JC, Robertson JF, Ellis IO, Williams T, Nicholson RI, Hurst HC. Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti-hormone therapy and reduced patient survival. J Pathol. 2009;217(1):32–41.CrossRefPubMed
45.
Penna E, Orso F, Cimino D, Tenaglia E, Lembo A, Quaglino E, Poliseno L, Haimovic A, Osella-Abate S, De Pitta C, et al. microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C. EMBO J. 2011;30(10):1990–2007.CrossRefPubMedPubMedCentral
46.
Lin CY, Chao A, Wang TH, Lee LY, Yang LY, Tsai CL, Wang HS, Lai CH. Nucleophosmin/B23 is a negative regulator of estrogen receptor alpha expression via AP2gamma in endometrial cancer cells. Oncotarget. 2016;7(37):60038–52.PubMedPubMedCentral
47.
Bogachek MV, Chen Y, Kulak MV, Woodfield GW, Cyr AR, Park JM, Spanheimer PM, Li Y, Li T, Weigel RJ. Sumoylation pathway is required to maintain the basal breast cancer subtype. Cancer Cell. 2014;25(6):748–61.CrossRefPubMedPubMedCentral
48.
Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee JT, Avruch J, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16(5):425–38.CrossRefPubMedPubMedCentral
49.
Ren A, Yan G, You B, Sun J. Down-regulation of mammalian sterile 20-like kinase 1 by heat shock protein 70 mediates cisplatin resistance in prostate cancer cells. Cancer Res. 2008;68(7):2266–74.CrossRefPubMed
50.
Kawahara M, Hori T, Chonabayashi K, Oka T, Sudol M, Uchiyama T. Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73. Blood. 2008;112(9):3856–66.CrossRefPubMed
51.
Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB, group AS, Bowtell DD, Harvey KF. The hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene. 2011;30(25):2810–22.CrossRefPubMed
52.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 2006;103(33):12405–10.CrossRefPubMedPubMedCentral
53.
Lai D, Ho KC, Hao Y, Yang X. Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res. 2011;71(7):2728–38.CrossRefPubMed
54.
Cao Z, Carey TS, Ganguly A, Wilson CA, Paul S, Knott JG. Transcription factor AP-2gamma induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage. Development. 2015;142(9):1606–15.CrossRefPubMedPubMedCentral
55.
Powe DG, Akhtar G, Habashy HO, Abdel-Fatah T, Rakha EA, Green AR, Ellis IO. Investigating AP-2 and YY1 protein expression as a cause of high HER2 gene transcription in breast cancers with discordant HER2 gene amplification. Breast cancer res. 2009;11(6):R90.CrossRefPubMedPubMedCentral
Metadata
Title
TFAP2C promotes stemness and chemotherapeutic resistance in colorectal cancer via inactivating hippo signaling pathway
Authors
Xu Wang
Di Sun
Jiandong Tai
Si Chen
Miao Yu
Dong Ren
Lei Wang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0683-9

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

Over-expression of oncigenic pesudogene DUXAP10 promotes cell proliferation and invasion by regulating LATS1 and β-catenin in gastric cancer

Research

MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis

Research

Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/β-catenin-Lin28/let7-PDK1 cascade

Research

Liquid biopsy in mice bearing colorectal carcinoma xenografts: gateways regulating the levels of circulating tumor DNA (ctDNA) and miRNA (ctmiRNA)

Research

TSSC3 promotes autophagy via inactivating the Src-mediated PI3K/Akt/mTOR pathway to suppress tumorigenesis and metastasis in osteosarcoma, and predicts a favorable prognosis

Review

Role of the nervous system in cancer metastasis
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