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01-05-2016 | Original Article

Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer

Authors: Jing Guo, Xiaofang Yu, Jie Gu, Zongwu Lin, Guangyin Zhao, Fengkai Xu, Chunlai Lu, Di Ge

Published in: Tumor Biology | Issue 5/2016

Abstract

CXC chemokines and their cognate receptors have been implicated wildly in cancer pathogenesis. In the present study, we report a critical cause relationship between CXCR4 expression and tumorigenesis in the setting of human esophageal squamous cell carcinoma (ESCC). In ESCC cells, CXCR4 expression was significantly higher than in human esophageal epithelial cells (HEEC). Reduction of CXCR4 in ESCC cells reduced cell proliferation and invasion in vitro and tumor growth in vivo. Among the potential downstream targets of CXCR4-CXCL12 are RhoA, Rac-1, and Cdc42, which are likely to contribute to the invasiveness of ESCC cells. Finally, we found that CXCR4-CXCL12/AKT axis regulates RhoA, Rac-1, and Cdc42 to modulate cell invasion and tumor metastasis. Together, these results demonstrate a role for CXCR4 in ESCC metastasis and progression and suggest potential targets for therapeutic intervention.

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Chen G, Wang Z, Liu XY, Liu FY. Recurrence pattern of squamous cell carcinoma in the middle thoracic esophagus after modified Ivor-Lewis esophagectomy. World J Surg. 2007;31(5):1107–14.CrossRefPubMed

Dresner SM, Griffin SM. Pattern of recurrence following radical oesophagectomy with two-field lymphadenectomy. Br J Surg. 2000;87(10):1426–33.CrossRefPubMed

Chen WQ, Zheng RS, Zhang SW, Zeng HM, Zou XN. The incidences and mortalities of major cancers in China, 2010. Chin J Cancer. 2014;33(8):402–5.PubMedPubMedCentral

Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am. 2002;11(2):235–56.CrossRefPubMed

Lu CL, Ji Y, Ge D, Guo J, Ding JY. The expression of CXCR4 and its relationship with matrix metalloproteinase-9/vascular endothelial growth factor in esophageal squamous cell cancer. Dis Esophagus. 2011;24(4):283–90.CrossRefPubMed

Lu CL, Guo J, Gu J, Ge D, Hou YY, Lin ZW, et al. CXCR4 heterogeneous expression in esophageal squamous cell cancer and stronger metastatic potential with CXCR4-positive cancer cells. Dis Esophagus. 2014;27(3):294–302.CrossRefPubMed

Wu J, Wu X, Liang W, Chen C, Zheng L, An H. Clinicopathological and prognostic significance of chemokine receptor CXCR4 overexpression in patients with esophageal cancer: a meta-analysis. Tumour Biol. 2014;35(4):3709–15.CrossRefPubMed

Gockel I, Schimanski CC, Heinrich C, Wehler T, Frerichs K, Drescher D, et al. Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma. BMC Cancer. 2006;6:290.CrossRefPubMedPubMedCentral

Faried A, Faried LS, Usman N, Kato H, Kuwano H. Clinical and prognostic significance of RhoA and RhoC gene expression in esophageal squamous cell carcinoma. Ann Surg Oncol. 2007;14(12):3593–601.CrossRefPubMed

10.

Yang Q, Luo GY, Li Y, Shan HB, Wang HY, Xu GL. Expression of Rac-1 related to tumor depth, lymph node metastasis and patient prognosis in esophageal squamous cell carcinoma. Med Oncol. 2013;30(4):689.CrossRefPubMed

11.

Zhao ZH, Tian Y, Yang JP, Zhou J, Chen KS. RhoC, vascular endothelial growth factor and microvascular density in esophageal squamous cell carcinoma. World J Gastroenterol. 2015;21(3):905–12.CrossRefPubMedPubMedCentral

12.

Lv B, Yang X, Lv S, Wang L, Fan K, Shi R et al. CXCR4 Signaling induced epithelial-mesenchymal transition by PI3K/AKT and ERK pathways in glioblastoma. Mol Neurobiol. 2014.

13.

Yang P, Wang G, Huo H, Li Q, Zhao Y, Liu Y. SDF-1/CXCR4 signaling up-regulates survivin to regulate human sacral chondrosarcoma cell cycle and epithelial-mesenchymal transition via ERK and PI3K/AKT pathway. Med Oncol. 2015;32(1):377.CrossRefPubMed

14.

Ponomaryov T, Peled A, Petit I, Taichman RS, Habler L, Sandbank J, et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest. 2000;106(11):1331–9.CrossRefPubMedPubMedCentral

15.

Wang J, Wang J, Dai J, Jung Y, Wei CL, Wang Y, et al. A glycolytic mechanism regulating an angiogenic switch in prostate cancer. Cancer Res. 2007;67(1):149–59.CrossRefPubMed

16.

Kato M, Kitayama J, Kazama S, Nagawa H. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res. 2003;5(5):R144–50.CrossRefPubMedPubMedCentral

17.

Wang J, Cai J, Han F, Yang C, Tong Q, Cao T, et al. Silencing of CXCR4 blocks progression of ovarian cancer and depresses canonical Wnt signaling pathway. Int J Gynecol Cancer. 2011;21(6):981–7.CrossRefPubMed

18.

Scala S, Ottaiano A, Ascierto PA, Cavalli M, Simeone E, Giuliano P, et al. Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(5):1835–41.CrossRef

19.

Spano JP, Andre F, Morat L, Sabatier L, Besse B, Combadiere C, et al. Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome. Ann Oncol. 2004;15(4):613–7.CrossRefPubMed

20.

Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med. 1999;5(2):221–5.CrossRefPubMed

21.

Clark EA, Golub TR, Lander ES, Hynes RO. Genomic analysis of metastasis reveals an essential role for RhoC. Nature. 2000;406(6795):532–5.CrossRefPubMed

22.

Ridley AJ. Rho GTPases and cell migration. J Cell Sci. 2001;114(Pt 15):2713–22.PubMed

23.

Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420(6916):629–35.CrossRefPubMed

24.

Sahai E, Marshall CJ. RHO-GTPases and cancer. Nat Rev Cancer. 2002;2(2):133–42.CrossRefPubMed

25.

Lin ML, Lu YC, Chen HY, Lee CC, Chung JG, Chen SS. Suppressing the formation of lipid raft-associated Rac1/PI3K/Akt signaling complexes by curcumin inhibits SDF-1alpha-induced invasion of human esophageal carcinoma cells. Mol Carcinog. 2014;53(5):360–79.CrossRefPubMed

26.

Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A. 2003;100(23):13513–8.CrossRefPubMedPubMedCentral

27.

Zou W, Machelon V, Coulomb-L'Hermin A, Borvak J, Nome F, Isaeva T, et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med. 2001;7(12):1339–46.CrossRefPubMed

Title: Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer
Authors: Jing Guo
Xiaofang Yu
Jie Gu
Zongwu Lin
Guangyin Zhao
Fengkai Xu
Chunlai Lu
Di Ge
Publication date: 01-05-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 5/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4504-x

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