Knockdown of CD44 Inhibits the Invasion and Metastasis of Hepatocellular Carcinoma Both in Vitro and in Vivo by Reversing Epithelial-mesenchymal Transition

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Mar 24

PMID 25797261

Citations 45

Authors

Yuan Gao

Bai Ruan

Weihui Liu

Jianlin Wang

Xisheng Yang

Zhuochao Zhang

Xia Li

Juanli Duan

Fuqing Zhang

Rui Ding

Kaishan Tao

Kefeng Dou

Affiliations

Soon will be listed here.

Abstract

Mounting evidence has shown that induction of epithelial-mesenchymal transition (EMT) contributes to the the expression of CSC (cancer stem cell) markers. However, whether and how CSC markers could be involved in regulating EMT has rarely been reported. CD44, being one of the most commonly used CSC markers in hepatocellular carcinoma (HCC), has been demonstrated to act as a multidomain, transmembrane platform that serves to integrate a wide variety of extracellular signals. Therefore, we determined to seek whether CD44 is necessary for the EMT process in HCC. First, we noticed that CD44 expression was associated with the mesenchymal phenotype in HCC cell lines, and knocking down CD44 with lentivirus-mediated shRNA in HCC cell lines resulted in the mesenchymal-epithelial-transition (MET) and the subsequent impaired migration and invasion in vitro. Moreover, in a metastatic mice model established by tail vein injection of luciferase labelled MHCC97-H cells, we confirmed that CD44 knockdown resulted in the decreased metastasis of HCC cells. Furthermore, we found that the induction of MET by CD44 inhibition might be achieved, at least in part, by repressing the ERK/Snail pathway.

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References

Bourguignon L, Gilad E, Rothman K, Peyrollier K . Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression. J Biol Chem. 2005; 280(12):11961-72. DOI: 10.1074/jbc.M411985200. View

Gos M, Miloszewska J, Przybyszewska M . [Epithelial-mesenchymal transition in cancer progression]. Postepy Biochem. 2009; 55(2):121-8. View

Forner A, Llovet J, Bruix J . Hepatocellular carcinoma. Lancet. 2012; 379(9822):1245-55. DOI: 10.1016/S0140-6736(11)61347-0. View

Chaffer C, Weinberg R . A perspective on cancer cell metastasis. Science. 2011; 331(6024):1559-64. DOI: 10.1126/science.1203543. View

Puisieux A, Brabletz T, Caramel J . Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014; 16(6):488-94. DOI: 10.1038/ncb2976. View

Orian-Rousseau V, Chen L, Sleeman J, Herrlich P, Ponta H . CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev. 2002; 16(23):3074-86. PMC: 187488. DOI: 10.1101/gad.242602. View

Hsu Y, Hou M, Kuo P, Huang Y, Tsai E . Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/snail signaling pathway. Oncogene. 2012; 32(37):4436-47. DOI: 10.1038/onc.2012.444. View

Polyak K, Weinberg R . Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009; 9(4):265-73. DOI: 10.1038/nrc2620. View

Makrodouli E, Oikonomou E, Koc M, Andera L, Sasazuki T, Shirasawa S . BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study. Mol Cancer. 2011; 10:118. PMC: 3189908. DOI: 10.1186/1476-4598-10-118. View

10.

Kong C, Wang C, Wang L, Ma M, Niu C, Sun X . NEDD9 is a positive regulator of epithelial-mesenchymal transition and promotes invasion in aggressive breast cancer. PLoS One. 2011; 6(7):e22666. PMC: 3145662. DOI: 10.1371/journal.pone.0022666. View

11.

Yang J, Mani S, Liu Donaher J, Ramaswamy S, Itzykson R, Come C . Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004; 117(7):927-39. DOI: 10.1016/j.cell.2004.06.006. View

12.

Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H . CD44s regulates the TGF-β-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res. 2012; 72(13):3414-23. DOI: 10.1158/0008-5472.CAN-12-0299. View

13.

Wang D, Lu P, Zhang H, Luo M, Zhang X, Wei X . Oct-4 and Nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients. Oncotarget. 2014; 5(21):10803-15. PMC: 4279411. DOI: 10.18632/oncotarget.2506. View

14.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J . The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000; 2(2):84-9. DOI: 10.1038/35000034. View

15.

Takahashi E, Nagano O, Ishimoto T, Yae T, Suzuki Y, Shinoda T . Tumor necrosis factor-alpha regulates transforming growth factor-beta-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction. J Biol Chem. 2009; 285(6):4060-4073. PMC: 2823547. DOI: 10.1074/jbc.M109.056523. View

16.

Tovuu L, Imura S, Utsunomiya T, Morine Y, Ikemoto T, Arakawa Y . Role of CD44 expression in non-tumor tissue on intrahepatic recurrence of hepatocellular carcinoma. Int J Clin Oncol. 2012; 18(4):651-6. DOI: 10.1007/s10147-012-0432-6. View

17.

Katsuno Y, Lamouille S, Derynck R . TGF-β signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol. 2012; 25(1):76-84. DOI: 10.1097/CCO.0b013e32835b6371. View

18.

Hou Y, Zou Q, Ge R, Shen F, Wang Y . The critical role of CD133(+)CD44(+/high) tumor cells in hematogenous metastasis of liver cancers. Cell Res. 2011; 22(1):259-72. PMC: 3351911. DOI: 10.1038/cr.2011.139. View

19.

Blick T, Hugo H, Widodo E, Waltham M, Pinto C, Mani S . Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia. 2010; 15(2):235-52. DOI: 10.1007/s10911-010-9175-z. View

20.

Zhou L, Wang D, Li Q, Sun W, Zhang Y, Dou K . The down-regulation of Notch1 inhibits the invasion and migration of hepatocellular carcinoma cells by inactivating the cyclooxygenase-2/Snail/E-cadherin pathway in vitro. Dig Dis Sci. 2012; 58(4):1016-25. DOI: 10.1007/s10620-012-2434-7. View