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Cancer Cell International
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Metastasis | Primary research

Absence of EpCAM in cervical cancer cells is involved in slug induced epithelial-mesenchymal transition

Authors: Xian Liu, Qian Feng, Yanru Zhang, PengSheng Zheng, Nan Cui

Published in: Cancer Cell International | Issue 1/2021

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Abstract

Background

Slug (Snai2) is a pivotal player in initiating epithelial-mesenchymal transition (EMT) through its trans-suppression effect on E-cadherin in various normal and malignant cells. In this study, the positive effect of Slug on promoting cell motility and metastasis in cervical cancer was further confirmed in this study.

Methods

RNA-Seq was performed to explore the potential molecules that participate in Slug-mediated EMT in cervical cancer cells. The negative correlation between Slug and EpCAM expression in cervical cancer cells was detected in this study, and linked them with in vitro migration and invasion assay, in vivo metastasis experiments, luciferase reporter assay and Chromatin immunoprecipitation.

Results

Transcriptome sequencing analysis revealed that epithelial cell adhesion molecule (EpCAM) was significantly decreased in Slug-overexpressing SiHa cells. Simultaneously, an absence of EpCAM expression was observed in Slug-overexpressing cells. Further studies revealed the trans-suppression effect of Slug on EpCAM through its binding to the E-boxes in the proximal promoter region of EpCAM in cervical cancer cells. Restoring EpCAM in Slug-overexpressing cells by transiently transfecting an EpCAM recombinant plasmid attenuated cell motility and promoted cell growth. Moreover, the negative correlation between Slug and EpCAM expression in human squamous cervical carcinoma (SCC) samples was verified by using Pearson correlation analysis.

Conclusions

These results demonstrated that the absence of EpCAM under Slug expression in cervical cancer cells probably participated in Slug-regulated EMT and further promoted tumor metastasis. Additionally, this study supports a potential way for Slug to initiate EMT progression in cervical cancer cells in addition to inhibiting E-cadherin.
Appendix
Available only for authorised users
Literature
1.
Ju J, Chen A, Deng Y, Liu M, Wang Y, Wang Y, Nie M, Wang C, Ding H, Yao B, et al. NatD promotes lung cancer progression by preventing histone H4 serine phosphorylation to activate Slug expression. Nat Commun. 2017;8(1):928.CrossRef
2.
Come C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, Savagner P. Snail and slug play distinct roles during breast carcinoma progression. Clinical cancer research: an official journal of the American Association for Cancer Research. 2006;12(18):5395–402.CrossRef
3.
Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer research. 2002;62(6):1613–8.PubMed
4.
Lin CW, Wang LK, Wang SP, Chang YL, Wu YY, Chen HY, Hsiao TH, Lai WY, Lu HH, Chang YH, et al. Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1alpha/HDAC1/Slug axis. Nat Commun. 2016;7:13867.CrossRef
5.
Meng J, Ai X, Lei Y, Zhong W, Qian B, Qiao K, Wang X, Zhou B, Wang H, Huai L, et al. USP5 promotes epithelial-mesenchymal transition by stabilizing SLUG in hepatocellular carcinoma. Theranostics. 2019;9(2):573–87.CrossRef
6.
Jiang B, Sun R, Fang S, Qin C, Pan X, Peng L, Li Y, Li G. Lnc-CC3 increases metastasis in cervical cancer by increasing Slug expression. Oncotarget. 2016;7(27):41650–61.CrossRef
7.
8.
Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc Natl Acad Sci USA. 1979;76(3):1438–42.CrossRef
9.
Baeuerle PA, Gires O. EpCAM (CD326) finding its role in cancer. Br J Cancer. 2007;96(3):417–23.CrossRef
10.
Mohtar MA, Syafruddin SE, Nasir SN, Low TY. Revisiting the Roles of Pro-Metastatic EpCAM in Cancer. Biomolecules. 2020;10(2):255.CrossRef
11.
Lei Z, Maeda T, Tamura A, Nakamura T, Yamazaki Y, Shiratori H, Yashiro K, Tsukita S, Hamada H. EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins. Developmental biology. 2012;371(2):136–45.CrossRef
12.
Gaiser MR, Lämmermann T, Feng X, Igyarto BZ, Kaplan DH, Tessarollo L, Germain RN, Udey MC. Cancer-associated epithelial cell adhesion molecule (EpCAM; CD326) enables epidermal Langerhans cell motility and migration in vivo. Proc Natl Acad Sci USA. 2012;109(15):E889–97.CrossRef
13.
Keller L, Werner S, Pantel K. Biology and clinical relevance of EpCAM. Cell stress. 2019;3(6):165–80.CrossRef
14.
Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA. 2010;107(35):15449–54.CrossRef
15.
Hyun KA, Koo GB, Han H, Sohn J, Choi W, Kim SI, Jung HI, Kim YS. Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer. Oncotarget. 2016;7(17):24677–87.CrossRef
16.
Sankpal NV, Fleming TP, Sharma PK, Wiedner HJ, Gillanders WE. A double-negative feedback loop between EpCAM and ERK contributes to the regulation of epithelial-mesenchymal transition in cancer. Oncogene. 2017;36(26):3706–17.CrossRef
17.
Lin CW, Liao MY, Lin WW, Wang YP, Lu TY, Wu HC. Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition gene expression in colon cancer. J Biol Chem. 2012;287(47):39449–59.CrossRef
18.
Gao J, Yan Q, Wang J, Liu S, Yang X. Epithelial-to-mesenchymal transition induced by TGF-beta1 is mediated by AP1-dependent EpCAM expression in MCF-7 cells. Journal of cellular physiology. 2015;230(4):775–82.CrossRef
19.
Chantima W, Thepthai C, Cheunsuchon P, Dharakul T. EpCAM expression in squamous cell carcinoma of the uterine cervix detected by monoclonal antibody to the membrane-proximal part of EpCAM. BMC Cancer. 2017;17(1):811.CrossRef
20.
Imadome K, Iwakawa M, Nakawatari M, Fujita H, Kato S, Ohno T, Nakamura E, Ohkubo Y, Tamaki T, Kiyohara H, et al. Subtypes of cervical adenosquamous carcinomas classified by EpCAM expression related to radiosensitivity. Cancer Biol Ther. 2010;10(10):1019–26.CrossRef
21.
Cui N, Yang WT, Zheng PS. Slug inhibits the proliferation and tumor formation of human cervical cancer cells by up-regulating the p21/p27 proteins and down-regulating the activity of the Wnt/beta-catenin signaling pathway via the trans-suppression Akt1/p-Akt1 expression. Oncotarget. 2016; 7(18):26152–26167.
22.
Xie Y, Liu S, Lu W, Yang Q, Williams KD, Binhazim AA, Carver BS, Matusik RJ, Chen Z. Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis. Molecular oncology. 2014;8(7):1355–64.CrossRef
23.
Cheng JC, Chang HM, Leung PC. Egr-1 mediates epidermal growth factor-induced downregulation of E-cadherin expression via Slug in human ovarian cancer cells. Oncogene. 2013;32(8):1041–9.CrossRef
24.
Wu Y, Gu TT, Zheng PS. CIP2A cooperates with H-Ras to promote epithelial-mesenchymal transition in cervical-cancer progression. Cancer letters. 2015;356(2 Pt B):646–55.CrossRef
25.
Hsu YT, Osmulski P, Wang Y, Huang YW, Liu L, Ruan J, Jin VX, Kirma NB, Gaczynska ME, Huang TH. EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition. Cancer research. 2016;76(21):6171–82.CrossRef
26.
Chaves-Perez A, Mack B, Maetzel D, Kremling H, Eggert C, Harreus U, Gires O. EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene. 2013;32(5):641–50.CrossRef
27.
Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, Kieu C, Papior P, Baeuerle PA, Munz M, et al. Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol. 2009;11(2):162–71.CrossRef
28.
Liu TY, Chen J, Shang CL, Shen HW, Huang JM, Liang YC, Wang W, Zhao YH, Liu D, Shu M, et al. Tripartite motif containing 62 is a novel prognostic marker and suppresses tumor metastasis via c-Jun/Slug signaling-mediated epithelial-mesenchymal transition in cervical cancer. Journal of experimental clinical cancer research: CR. 2016;35(1):170.CrossRef
29.
Wu DW, Lee MC, Wang J, Chen CY, Cheng YW, Lee H. DDX3 loss by p53 inactivation promotes tumor malignancy via the MDM2/Slug/E-cadherin pathway and poor patient outcome in non-small-cell lung cancer. Oncogene. 2014;33(12):1515–26.CrossRef
30.
Zhao L, Chen W, Taylor KM, Cai B, Li X. LIV-1 suppression inhibits HeLa cell invasion by targeting ERK1/2-Snail/Slug pathway. Biochem Biophys Res Commun. 2007;363(1):82–8.CrossRef
Metadata
Title
Absence of EpCAM in cervical cancer cells is involved in slug induced epithelial-mesenchymal transition
Authors
Xian Liu
Qian Feng
Yanru Zhang
PengSheng Zheng
Nan Cui
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-01858-3

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