Lysophosphatidic Acid Activates Arf6 to Promote the Mesenchymal Malignancy of Renal Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Feb 9

PMID 26854204

Citations 57

Authors

Shigeru Hashimoto

Shuji Mikami

Hirokazu Sugino

Ayumu Yoshikawa

Ari Hashimoto

Yasuhito Onodera

Shotaro Furukawa

Haruka Handa

Tsukasa Oikawa

Yasunori Okada

Mototsugu Oya

Hisataka Sabe

Affiliations

Soon will be listed here.

Abstract

Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial-mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-Gα12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients.

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References

Ridley A, Hall A . The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992; 70(3):389-99. DOI: 10.1016/0092-8674(92)90163-7. View

De Craene B, Berx G . Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013; 13(2):97-110. DOI: 10.1038/nrc3447. View

Onodera Y, Hashimoto S, Hashimoto A, Morishige M, Mazaki Y, Yamada A . Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities. EMBO J. 2005; 24(5):963-73. PMC: 554134. DOI: 10.1038/sj.emboj.7600588. View

Hafner M, Schmitz A, Grune I, Srivatsan S, Paul B, Kolanus W . Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature. 2006; 444(7121):941-4. DOI: 10.1038/nature05415. View

Morishige M, Hashimoto S, Ogawa E, Toda Y, Kotani H, Hirose M . GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion. Nat Cell Biol. 2007; 10(1):85-92. DOI: 10.1038/ncb1672. View

CAILLEAU R, Mackay B, YOUNG R, REEVES Jr W . Tissue culture studies on pleural effusions from breast carcinoma patients. Cancer Res. 1974; 34(4):801-9. View

Huang D, Ding Y, Li Y, Luo W, Zhang Z, Snider J . Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma. Cancer Res. 2010; 70(3):1053-62. DOI: 10.1158/0008-5472.CAN-09-3722. View

Frew I, Moch H . A clearer view of the molecular complexity of clear cell renal cell carcinoma. Annu Rev Pathol. 2014; 10:263-89. DOI: 10.1146/annurev-pathol-012414-040306. View

Stassar M, Devitt G, BROSIUS M, Rinnab L, Prang J, Schradin T . Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br J Cancer. 2001; 85(9):1372-82. PMC: 2375251. DOI: 10.1054/bjoc.2001.2074. View

10.

Donaldson J, Jackson C . ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat Rev Mol Cell Biol. 2011; 12(6):362-75. PMC: 3245550. DOI: 10.1038/nrm3117. View

11.

Wolf K, Mazo I, Leung H, Engelke K, von Andrian U, Deryugina E . Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol. 2003; 160(2):267-77. PMC: 2172637. DOI: 10.1083/jcb.200209006. View

12.

Aittaleb M, Boguth C, Tesmer J . Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors. Mol Pharmacol. 2009; 77(2):111-25. PMC: 2812070. DOI: 10.1124/mol.109.061234. View

13.

Rini B, Campbell S, Escudier B . Renal cell carcinoma. Lancet. 2009; 373(9669):1119-32. DOI: 10.1016/S0140-6736(09)60229-4. View

14.

Fuhrman S, Lasky L, Limas C . Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982; 6(7):655-63. DOI: 10.1097/00000478-198210000-00007. View

15.

Friedl P, Wolf K . Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003; 3(5):362-74. DOI: 10.1038/nrc1075. View

16.

Hirano M, Hashimoto S, Yonemura S, Sabe H, Aizawa S . EPB41L5 functions to post-transcriptionally regulate cadherin and integrin during epithelial-mesenchymal transition. J Cell Biol. 2008; 182(6):1217-30. PMC: 2542480. DOI: 10.1083/jcb.200712086. View

17.

Gerlinger M, Rowan A, Horswell S, Math M, Larkin J, Endesfelder D . Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366(10):883-892. PMC: 4878653. DOI: 10.1056/NEJMoa1113205. View

18.

Casanova J . Regulation of Arf activation: the Sec7 family of guanine nucleotide exchange factors. Traffic. 2007; 8(11):1476-85. DOI: 10.1111/j.1600-0854.2007.00634.x. View

19.

Hashimoto S, Onodera Y, Hashimoto A, Tanaka M, Hamaguchi M, Yamada A . Requirement for Arf6 in breast cancer invasive activities. Proc Natl Acad Sci U S A. 2004; 101(17):6647-52. PMC: 404099. DOI: 10.1073/pnas.0401753101. View

20.

Sato H, Hatanaka K, Hatanaka Y, Hatakeyama H, Hashimoto A, Matsuno Y . High level expression of AMAP1 protein correlates with poor prognosis and survival after surgery of head and neck squamous cell carcinoma patients. Cell Commun Signal. 2014; 12:17. PMC: 3995662. DOI: 10.1186/1478-811X-12-17. View