Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma

Authors: Guangbing Xiong, Hua Huang, Mengyu Feng, Gang Yang, Suli Zheng, Lei You, Lianfang Zheng, Ya Hu, Taiping Zhang, Yupei Zhao

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

Login to get access

Abstract

Background

By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear.

Methods

The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated.

Results

We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC.

Conclusion

Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.
Appendix
Available only for authorised users
Literature
1.
2.
go back to reference Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.CrossRefPubMedPubMedCentral Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.CrossRefPubMedPubMedCentral
3.
go back to reference Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.CrossRefPubMed Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.CrossRefPubMed
4.
go back to reference Xiong G, Feng M, Yang G, Zheng S, Song X, Cao Z, You L, Zheng L, Hu Y, Zhang T, et al. The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer. Cancer Lett. 2017;397:94–102.CrossRefPubMed Xiong G, Feng M, Yang G, Zheng S, Song X, Cao Z, You L, Zheng L, Hu Y, Zhang T, et al. The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer. Cancer Lett. 2017;397:94–102.CrossRefPubMed
5.
go back to reference Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu CG, Bhatt D, Taccioli C, Croce CM. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297(17):1901–8.CrossRefPubMed Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu CG, Bhatt D, Taccioli C, Croce CM. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297(17):1901–8.CrossRefPubMed
6.
go back to reference Ohuchida K, Mizumoto K, Lin C, Yamaguchi H, Ohtsuka T, Sato N, Toma H, Nakamura M, Nagai E, Hashizume M, et al. MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene. Ann Surg Oncol. 2012;19(7):2394–402.CrossRefPubMed Ohuchida K, Mizumoto K, Lin C, Yamaguchi H, Ohtsuka T, Sato N, Toma H, Nakamura M, Nagai E, Hashizume M, et al. MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene. Ann Surg Oncol. 2012;19(7):2394–402.CrossRefPubMed
7.
go back to reference Wang Y, Liu Z, Yao B, Dou C, Xu M, Xue Y, Ding L, Jia Y, Zhang H, Li Q, et al. Long non-coding RNA TUSC7 acts a molecular sponge for miR-10a and suppresses EMT in hepatocellular carcinoma. Tumour Biol. 2016;37(8):11429–41.CrossRefPubMedPubMedCentral Wang Y, Liu Z, Yao B, Dou C, Xu M, Xue Y, Ding L, Jia Y, Zhang H, Li Q, et al. Long non-coding RNA TUSC7 acts a molecular sponge for miR-10a and suppresses EMT in hepatocellular carcinoma. Tumour Biol. 2016;37(8):11429–41.CrossRefPubMedPubMedCentral
8.
go back to reference Yu T, Liu L, Li J, Yan M, Lin H, Liu Y, Chu D, Tu H, Gu A, Yao M. MiRNA-10a is upregulated in NSCLC and may promote cancer by targeting PTEN. Oncotarget. 2015;6(30):30239–50.CrossRefPubMedPubMedCentral Yu T, Liu L, Li J, Yan M, Lin H, Liu Y, Chu D, Tu H, Gu A, Yao M. MiRNA-10a is upregulated in NSCLC and may promote cancer by targeting PTEN. Oncotarget. 2015;6(30):30239–50.CrossRefPubMedPubMedCentral
9.
go back to reference Chang CH, Fan TC, Yu JC, Liao GS, Lin YC, Shih AC, Li WH, Yu AL. The prognostic significance of RUNX2 and miR-10a/10b and their inter-relationship in breast cancer. J Transl Med. 2014;12:257.CrossRefPubMedPubMedCentral Chang CH, Fan TC, Yu JC, Liao GS, Lin YC, Shih AC, Li WH, Yu AL. The prognostic significance of RUNX2 and miR-10a/10b and their inter-relationship in breast cancer. J Transl Med. 2014;12:257.CrossRefPubMedPubMedCentral
10.
go back to reference Long MJ, Wu FX, Li P, Liu M, Li X, Tang H. MicroRNA-10a targets CHL1 and promotes cell growth, migration and invasion in human cervical cancer cells. Cancer Lett. 2012;324(2):186–96.CrossRefPubMed Long MJ, Wu FX, Li P, Liu M, Li X, Tang H. MicroRNA-10a targets CHL1 and promotes cell growth, migration and invasion in human cervical cancer cells. Cancer Lett. 2012;324(2):186–96.CrossRefPubMed
11.
go back to reference Jia H, Zhang Z, Zou D, Wang B, Yan Y, Luo M, Dong L, Yin H, Gong B, Li Z, et al. MicroRNA-10a is down-regulated by DNA methylation and functions as a tumor suppressor in gastric cancer cells. PLoS One. 2014;9(1):e88057.CrossRefPubMedPubMedCentral Jia H, Zhang Z, Zou D, Wang B, Yan Y, Luo M, Dong L, Yin H, Gong B, Li Z, et al. MicroRNA-10a is down-regulated by DNA methylation and functions as a tumor suppressor in gastric cancer cells. PLoS One. 2014;9(1):e88057.CrossRefPubMedPubMedCentral
12.
go back to reference Khan S, Wall D, Curran C, Newell J, Kerin MJ, Dwyer RM. MicroRNA-10a is reduced in breast cancer and regulated in part through retinoic acid. BMC Cancer. 2015;15:345.CrossRefPubMedPubMedCentral Khan S, Wall D, Curran C, Newell J, Kerin MJ, Dwyer RM. MicroRNA-10a is reduced in breast cancer and regulated in part through retinoic acid. BMC Cancer. 2015;15:345.CrossRefPubMedPubMedCentral
13.
go back to reference Sun W, Ma Y, Chen P, Wang D. MicroRNA-10a silencing reverses cisplatin resistance in the A549/cisplatin human lung cancer cell line via the transforming growth factor-beta/Smad2/STAT3/STAT5 pathway. Mol Med Rep. 2015;11(5):3854–9.CrossRefPubMed Sun W, Ma Y, Chen P, Wang D. MicroRNA-10a silencing reverses cisplatin resistance in the A549/cisplatin human lung cancer cell line via the transforming growth factor-beta/Smad2/STAT3/STAT5 pathway. Mol Med Rep. 2015;11(5):3854–9.CrossRefPubMed
14.
go back to reference Hoppe R, Achinger-Kawecka J, Winter S, Fritz P, Lo WY, Schroth W, Brauch H. Increased expression of miR-126 and miR-10a predict prolonged relapse-free time of primary oestrogen receptor-positive breast cancer following tamoxifen treatment. Eur J Cancer. 2013;49(17):3598–608.CrossRefPubMed Hoppe R, Achinger-Kawecka J, Winter S, Fritz P, Lo WY, Schroth W, Brauch H. Increased expression of miR-126 and miR-10a predict prolonged relapse-free time of primary oestrogen receptor-positive breast cancer following tamoxifen treatment. Eur J Cancer. 2013;49(17):3598–608.CrossRefPubMed
15.
go back to reference Hudson J, Duncavage E, Tamburrino A, Salerno P, Xi L, Raffeld M, Moley J, Chernock RD. Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma. Exp Mol Pathol. 2013;95(1):62–7.CrossRefPubMedPubMedCentral Hudson J, Duncavage E, Tamburrino A, Salerno P, Xi L, Raffeld M, Moley J, Chernock RD. Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma. Exp Mol Pathol. 2013;95(1):62–7.CrossRefPubMedPubMedCentral
16.
go back to reference Chen W, Tang Z, Sun Y, Zhang Y, Wang X, Shen Z, Liu F, Qin X. miRNA expression profile in primary gastric cancers and paired lymph node metastases indicates that miR-10a plays a role in metastasis from primary gastric cancer to lymph nodes. Exp Ther Med. 2012;3(2):351–6.CrossRefPubMed Chen W, Tang Z, Sun Y, Zhang Y, Wang X, Shen Z, Liu F, Qin X. miRNA expression profile in primary gastric cancers and paired lymph node metastases indicates that miR-10a plays a role in metastasis from primary gastric cancer to lymph nodes. Exp Ther Med. 2012;3(2):351–6.CrossRefPubMed
17.
go back to reference Inoue N, Isomoto H, Matsushima K, Hayashi T, Kunizaki M, Hidaka S, Machida H, Mitsutake N, Nanashima A, Takeshima F, et al. Down-regulation of microRNA 10a expression in esophageal squamous cell carcinoma cells. Oncol Lett. 2010;1(3):527–31.CrossRefPubMedPubMedCentral Inoue N, Isomoto H, Matsushima K, Hayashi T, Kunizaki M, Hidaka S, Machida H, Mitsutake N, Nanashima A, Takeshima F, et al. Down-regulation of microRNA 10a expression in esophageal squamous cell carcinoma cells. Oncol Lett. 2010;1(3):527–31.CrossRefPubMedPubMedCentral
18.
go back to reference Li X, Zhang Y, Zhang Y, Ding J, Wu K, Fan D. Survival prediction of gastric cancer by a seven-microRNA signature. Gut. 2010;59(5):579–85.CrossRefPubMed Li X, Zhang Y, Zhang Y, Ding J, Wu K, Fan D. Survival prediction of gastric cancer by a seven-microRNA signature. Gut. 2010;59(5):579–85.CrossRefPubMed
19.
go back to reference Cyr AR, Kulak MV, Park JM, Bogachek MV, Spanheimer PM, Woodfield GW, White-Baer LS, O'Malley YQ, Sugg SL, Olivier AK, et al. TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis. Oncogene. 2015;34(4):436–44.CrossRefPubMed Cyr AR, Kulak MV, Park JM, Bogachek MV, Spanheimer PM, Woodfield GW, White-Baer LS, O'Malley YQ, Sugg SL, Olivier AK, et al. TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis. Oncogene. 2015;34(4):436–44.CrossRefPubMed
20.
go back to reference Spanheimer PM, Woodfield GW, Cyr AR, Kulak MV, White-Baer LS, Bair TB, Weigel RJ. Expression of the RET proto-oncogene is regulated by TFAP2C in breast cancer independent of the estrogen receptor. Ann Surg Oncol. 2013;20(7):2204–12.CrossRefPubMed Spanheimer PM, Woodfield GW, Cyr AR, Kulak MV, White-Baer LS, Bair TB, Weigel RJ. Expression of the RET proto-oncogene is regulated by TFAP2C in breast cancer independent of the estrogen receptor. Ann Surg Oncol. 2013;20(7):2204–12.CrossRefPubMed
21.
go back to reference Perkins SM, Bales C, Vladislav T, Althouse S, Miller KD, Sandusky G, Badve S, Nakshatri H. TFAP2C expression in breast cancer: correlation with overall survival beyond 10 years of initial diagnosis. Breast Cancer Res Treat. 2015;152(3):519–31.CrossRefPubMed Perkins SM, Bales C, Vladislav T, Althouse S, Miller KD, Sandusky G, Badve S, Nakshatri H. TFAP2C expression in breast cancer: correlation with overall survival beyond 10 years of initial diagnosis. Breast Cancer Res Treat. 2015;152(3):519–31.CrossRefPubMed
22.
go back to reference 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 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
23.
go back to reference 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 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
24.
go back to reference Chang TH, Tsai MF, Gow CH, Wu SG, Liu YN, Chang YL, Yu SL, Tsai HC, Lin SW, Chen YW, et al. Upregulation of microRNA-137 expression by slug promotes tumor invasion and metastasis of non-small cell lung cancer cells through suppression of TFAP2C. Cancer Lett. 2017;402:190–202.CrossRefPubMed Chang TH, Tsai MF, Gow CH, Wu SG, Liu YN, Chang YL, Yu SL, Tsai HC, Lin SW, Chen YW, et al. Upregulation of microRNA-137 expression by slug promotes tumor invasion and metastasis of non-small cell lung cancer cells through suppression of TFAP2C. Cancer Lett. 2017;402:190–202.CrossRefPubMed
Metadata
Title
MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma
Authors
Guangbing Xiong
Hua Huang
Mengyu Feng
Gang Yang
Suli Zheng
Lei You
Lianfang Zheng
Ya Hu
Taiping Zhang
Yupei Zhao
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/s13046-018-0739-x

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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