PADI1 Contributes to EMT in PAAD by Activating the ERK1/2-p38 Signaling Pathway

Overview

Journal J Gastrointest Oncol

Date 2021 Jul 23

PMID 34295566

Citations 8

Authors

Tengfei Ji

Keqiang Ma

Liang Chen

Tiansheng Cao

Affiliations

Soon will be listed here.

Abstract

Background: Peptidylarginine deiminase 1 (PADI1) has been reported to promote tumorigenesis in breast cancer. However, the functional role of PADI1 in pancreatic ductal adenocarcinoma (PAAD) has remained elusive until now.

Methods: The expression pattern of PADI1 in PAAD tissues and normal tissues was analyzed using The Cancer Genome Atlas (TCGA) dataset. A Kaplan-Meier curve analysis was performed to evaluate the prognostic value of PADI1 in PAAD patients. PADI1 was knocked down in CFPAN-1 and HPAC cells, and overexpressed in PANC-1 and Bxpc-3 cells by RNA interference. A wound-healing assay was performed to analyze relative cell migration distance. Cell migration and invasion were assessed by a Transwell assay. Related protein expression levels were measured by western blot and immunofluorescence.

Results: The bioinformatics analysis showed that PADI1 was overexpressed in PAAD tissues and associated with a poor survival prognosis. The knockdown of PADI1 suppressed cell migration and invasion, and activated the ERK1/2-p38 signaling pathway in CFPAN-1 and HPAC cells. The overexpression of PADI1 produced the opposite results in PANC-1 and Bxpc-3 cells. Additionally, treatment with an MEK1/2 inhibitor significantly attenuated the effects of PADI1 knockdown on cell migration, invasion, the epithelial-mesenchymal transition (EMT) process, and p-ERK1/2 and p38 expression in CFPAN-1 and HPAC cells.

Conclusions: Our data suggested that PADI1 may function as an oncogene in regulating metastasis in PAAD.

Citing Articles

Application of integrin subunit genes in pancreatic cancer and the construction of a prognosis model.

Ye Q, Zhou T, Liu X, Chen D, Yang B, Yu T J Gastrointest Oncol. 2024; 15(5):2286-2304.

PMID: 39554585 PMC: 11565112. DOI: 10.21037/jgo-24-612.

Targeting PADI2 as a potential therapeutic strategy against metastasis in oral cancer via suppressing EMT-mediated migration and invasion and CCL3/5-induced angiogenesis.

Hung S, Yu C, Lin H, Chiou W, Lee M, Lin R Clin Exp Metastasis. 2024; 41(6):925-935.

PMID: 39215870 DOI: 10.1007/s10585-024-10310-5.

The knockdown of lncRNA DLGAP1-AS2 suppresses osteosarcoma progression by inhibiting aerobic glycolysis via the miR-451a/HK2 axis.

Zheng C, Li R, Zheng S, Fang H, Xu M, Zhong L Cancer Sci. 2023; 114(12):4747-4762.

PMID: 37817462 PMC: 10728003. DOI: 10.1111/cas.15989.

Role of the PADI family in inflammatory autoimmune diseases and cancers: A systematic review.

Zhu C, Liu C, Chai Z Front Immunol. 2023; 14:1115794.

PMID: 37020554 PMC: 10067674. DOI: 10.3389/fimmu.2023.1115794.

LncRNA MBNL1-AS1 Suppresses Cell Proliferation and Metastasis of Pancreatic Adenocarcinoma through Targeting Carcinogenic miR-301b-3p.

Sulidankazha C, Alidake , Lin H, He T, Han W, Chen Q Genet Res (Camb). 2023; 2023:6785005.

PMID: 36908851 PMC: 9995204. DOI: 10.1155/2023/6785005.

References

Zhai Q, Qin J, Jin X, Sun X, Wang L, Du W . PADI4 modulates the invasion and migration of osteosarcoma cells by down-regulation of epithelial-mesenchymal transition. Life Sci. 2020; 256:117968. DOI: 10.1016/j.lfs.2020.117968. View

Miao J, Wang S, Zhang M, Yu F, Zhang L, Yu Z . Knockdown of galectin-1 suppresses the growth and invasion of osteosarcoma cells through inhibition of the MAPK/ERK pathway. Oncol Rep. 2014; 32(4):1497-504. DOI: 10.3892/or.2014.3358. View

Duan Q, Pang C, Chang N, Zhang J, Liu W . Overexpression of PAD4 suppresses drug resistance of NSCLC cell lines to gefitinib through inhibiting Elk1-mediated epithelial-mesenchymal transition. Oncol Rep. 2016; 36(1):551-8. DOI: 10.3892/or.2016.4780. View

Dhillon A, Hagan S, Rath O, Kolch W . MAP kinase signalling pathways in cancer. Oncogene. 2007; 26(22):3279-90. DOI: 10.1038/sj.onc.1210421. View

Chi J, Chung S, Parakrama R, Fayyaz F, Jose J, Saif M . The role of PARP inhibitors in mutated pancreatic cancer. Therap Adv Gastroenterol. 2021; 14:17562848211014818. PMC: 8120537. DOI: 10.1177/17562848211014818. View

Qin H, Liu X, Li F, Miao L, Li T, Xu B . PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling. Cancer Lett. 2017; 409:30-41. PMC: 5718050. DOI: 10.1016/j.canlet.2017.08.019. View

Zhu J, Zheng Y, Zhang H, Liu Y, Sun H, Zhang P . Galectin-1 induces metastasis and epithelial-mesenchymal transition (EMT) in human ovarian cancer cells via activation of the MAPK JNK/p38 signalling pathway. Am J Transl Res. 2019; 11(6):3862-3878. PMC: 6614631. View

Nielsen S, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A . Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol. 2016; 18(5):549-60. PMC: 4894551. DOI: 10.1038/ncb3340. View

Vossenaar E, Zendman A, van Venrooij W, Pruijn G . PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays. 2003; 25(11):1106-18. DOI: 10.1002/bies.10357. View

10.

Li Z, Liu X, Wang B, Nie Y, Wen J, Wang Q . Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton). 2016; 22(8):589-597. DOI: 10.1111/nep.12831. View

11.

Wang Y, Li P, Wang S, Hu J, Chen X, Wu J . Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J Biol Chem. 2012; 287(31):25941-53. PMC: 3406678. DOI: 10.1074/jbc.M112.375725. View

12.

Xin J, Song X . Role of peptidylarginine deiminase type 4 in gastric cancer. Exp Ther Med. 2016; 12(5):3155-3160. PMC: 5103760. DOI: 10.3892/etm.2016.3798. View

13.

Liu L, Zhang Z, Zhang G, Wang T, Ma Y, Guo W . Down-regulation of PADI2 prevents proliferation and epithelial-mesenchymal transition in ovarian cancer through inhibiting JAK2/STAT3 pathway in vitro and in vivo, alone or in combination with Olaparib. J Transl Med. 2020; 18(1):357. PMC: 7504643. DOI: 10.1186/s12967-020-02528-0. View

14.

Sheng W, Chen C, Dong M, Wang G, Zhou J, Song H . Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway. Cell Death Dis. 2017; 8(10):e3147. PMC: 5680916. DOI: 10.1038/cddis.2017.547. View

15.

Wang L, Song G, Zhang X, Feng T, Pan J, Chen W . PADI2-Mediated Citrullination Promotes Prostate Cancer Progression. Cancer Res. 2017; 77(21):5755-5768. DOI: 10.1158/0008-5472.CAN-17-0150. View

16.

Cheng J, Klausen C, Leung P . Hydrogen peroxide mediates EGF-induced down-regulation of E-cadherin expression via p38 MAPK and snail in human ovarian cancer cells. Mol Endocrinol. 2010; 24(8):1569-80. PMC: 5417450. DOI: 10.1210/me.2010-0034. View

17.

Chang X, Han J . Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog. 2005; 45(3):183-96. DOI: 10.1002/mc.20169. View

18.

Yilmaz M, Christofori G, Lehembre F . Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med. 2007; 13(12):535-41. DOI: 10.1016/j.molmed.2007.10.004. View

19.

Siegel R, Miller K, Jemal A . Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. DOI: 10.3322/caac.21442. View

20.

Liu M, Qu Y, Teng X, Xing Y, Li D, Li C . PADI4‑mediated epithelial‑mesenchymal transition in lung cancer cells. Mol Med Rep. 2019; 19(4):3087-3094. PMC: 6423585. DOI: 10.3892/mmr.2019.9968. View