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Vol. 18, Issue 11, 4210-4221, November 2007

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Dual Role of 64 Integrin in Epidermal Tumor Growth: Tumor-suppressive Versus Tumor-promoting Function

Karine Raymond^*, Maaike Kreft^*, Ji-Ying Song, Hans Janssen^*, and Arnoud Sonnenberg^*

*Division of Cell Biology and Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Submitted August 16, 2006; Revised July 28, 2007; Accepted August 7, 2007
Monitoring Editor: Martin A. Schwartz

An increased expression of the integrin 64 is correlated with a poor prognosis in patients with squamous cell carcinomas. However, little is known about the role of 64 in the early stages of tumor development. We have isolated cells from mouse skin (mouse tumor-initiating cells [mTICs]) that are deficient in both p53 and Smad4 and carry conditional alleles of the 4 gene (Itgb4). The mTICs display many features of multipotent epidermal stem cells and produce well-differentiated tumors after subcutaneous injection into nude mice. Deletion of Itgb4 led to enhanced tumor growth, indicating that 64 mediates a tumor-suppressive effect. Reconstitution experiments with 4-chimeras showed that this effect is not dependent on ligation of 64 to laminin-5, but on the recruitment by this integrin of the cytoskeletal linker protein plectin to the plasma membrane. Depletion of plectin, like that of 4, led to increased tumor growth. In contrast, when mTICs had been further transformed with oncogenic Ras, 64 stimulated tumor growth, as previously observed in human squamous neoplasms. Expression of different effector-loop mutants of Ras^V12 suggests that this effect depends on a strong activation of the Erk pathway. Together, these data show that depending on the mutations involved, 64 can either mediate an adhesion-independent tumor-suppressive effect or act as a tumor promotor.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Arnoud Sonnenberg (a.sonnenberg{at}nki.nl).

Abbreviations used: BCC, basal cell carcinoma; BM, basement membrane; BMP, bone morphogenic protein; BP, bullous pemphigoid; BrdU, 5-bromo-2-deoxyuridine; ECM, extracellular matrix; HD, hemidesmosome; HF, hair follicle; IF, intermediate filament; IFE, interfollicular epidermis; IRS, inner root sheath; K10, keratin-10; Ln-5, Laminin-5; mTIC, mouse tumor-initiating cell; ORS, outer root sheath; SC, stem cell; SCC, squamous cell carcinoma; TGF-, transforming growth factor .