Abstract
Overexpression of the basement membrane protein Laminin γ2 (Lamγ2) is a feature of many epidermal and oral dysplasias and all invasive squamous cell carcinomas (SCCs). This abnormality has potential value as an immunohistochemical biomarker of premalignancy but its mechanism has remained unknown. We recently reported that Lamγ2 overexpression in culture is the result of deregulated translation controls and depends on the MAPK-RSK signaling cascade. Here we identify eIF4B as the RSK downstream effector responsible for elevated Lamγ2 as well as MYC protein in neoplastic epithelial cells. Premalignant dysplastic keratinocytes, SCC cells, and keratinocytes expressing the E6 oncoprotein of human papillomavirus (HPV) type 16 displayed MAPK-RSK and mTOR-S6K1 activation and overexpressed Lamγ2 and MYC in culture. Immunohistochemical staining of oral dysplasias and SCCs for distinct, RSK- and S6K1-specific S6 phosphorylation events revealed that their respective upstream pathways become hyperactive at the same time during neoplastic progression. However, pharmacologic kinase inhibitor studies in culture revealed that Lamγ2 and MYC overexpression depends on MAPK-RSK activity, independent of PI3K-mTOR-S6K1. eIF4B knockdown reduced Lamγ2 and MYC protein expression, consistent with the known requirement for eIF4B to translate mRNAs with long, complex 5′ untranslated regions (5′-UTRs). Accordingly, expression of a luciferase reporter construct preceded by the Lamγ2 5′-UTR proved to be RSK-dependent and mTOR-independent. These results demonstrate that RSK activation of eIF4B is causally linked to elevated Lamγ2 and MYC protein levels during neoplastic progression to invasive SCC. These findings have potential clinical significance for identifying premalignant lesions and for developing targeted drugs to treat SCC.
Highlights
Squamous cell carcinoma (SCC) is an aggressive cancer that arises from stratified epithelia, including the epidermis and the bronchial, cervical, and oral epithelia
To extend our previous finding that Laminin c2 (Lamc2) and MYC overexpression correlated with MAPK pathway hyperactivity in SCC cells [21], we investigated more thoroughly the possibility of a role for the PI3K/mTOR pathway
We examined the effects on Lamc2 and MYC expression of PIK-75, an inhibitor of the PI3K subunit p110a [40], and of rapamycin, a specific inhibitor of mTORC1, comparing these to gefitinib, an inhibitor of EGFR kinase that can stimulate both the MAPK and PI3K signaling cascades (Fig. 1A)
Summary
Squamous cell carcinoma (SCC) is an aggressive cancer that arises from stratified epithelia, including the epidermis and the bronchial, cervical, and oral epithelia. Genetic alterations frequently present in advanced oral and oropharyngeal SCCs include mutations of TP53, CDKN2A, HRAS, PTEN, and PIK3CA and gene amplification of EGFR and MYC [2,3]. Many of these alterations result in activation of the MAPK pathway (i.e., RAS-RAF-MEK-RSK) or the PI3K-AKT-mTOR pathway, or both [2,3,4,5]. 6% of oral and a higher proportion of oropharyngeal SCCs involve infection with high-risk HPV types 16 or 18 and integration and expression of their E6 and E7 viral oncogenes [6,7,8], the activities of which can replace mutations in some of the genes listed above to confer neoplastic properties
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