Abstract
Podoplanin and CD44 are transmembrane glycoproteins involved in inflammation and cancer. In this paper, we report that podoplanin is coordinately expressed with the CD44 standard (CD44s) and variant (CD44v) isoforms in vivo—in hyperplastic skin after a pro-inflammatory stimulus with 12-O-tetradecanoylphorbol-13-acetate (TPA)—and in vitro—in cell lines representative of different stages of mouse-skin chemical carcinogenesis, as well as in human squamous carcinoma cell (SCC) lines. Moreover, we identify CD44v10 in the mouse-skin carcinogenesis model as the only CD44 variant isoform expressed in highly aggressive spindle carcinoma cell lines together with CD44s and podoplanin. We also characterized CD44v3-10, CD44v6-10 and CD44v8-10 as the major variant isoforms co-expressed with CD44s and podoplanin in human SCC cell lines. Immunofluorescence confocal microscopy experiments show that these CD44v isoforms colocalize with podoplanin at plasma membrane protrusions and cell–cell contacts of SCC cells, as previously reported for CD44s. Furthermore, CD44v isoforms colocalize with podoplanin in chemically induced mouse-skin SCCs in vivo. Co-immunoprecipitation experiments indicate that podoplanin physically binds to CD44v3-10, CD44v6-10 and CD44v8-10 isoforms, as well as to CD44s. Podoplanin–CD44 interaction is mediated by the transmembrane and cytosolic regions and is negatively modulated by glycosylation of the extracellular domain. These results point to a functional interplay of podoplanin with both CD44v and CD44s isoforms in SCCs and give insight into the regulation of the podoplanin–CD44 association.
Highlights
Squamous cell carcinoma (SCC) is one of the most frequent cancers worldwide
We found that podoplanin binds CD44 standard (CD44s) on cell-surface protrusions associated with motility of squamous carcinoma cell (SCC) cells and that both glycoproteins cooperate to promote directional migration of SCC cells [40]
In order to whether TPA was able to induce CD44 together with podoplanin in vivo, the skin of mice was treated ascertain whether TPA was able to induce CD44 together with podoplanin in vivo, the skin of mice withwas and the expression of podoplanin and CD44 analyzed by Western blotting at different times treated with TPA and the expression of podoplanin and CD44 analyzed by Western blotting at posttreatment
Summary
Squamous cell carcinoma (SCC) is one of the most frequent cancers worldwide. It arises in cells of stratified epithelia such as the epidermis, esophagus and mucosal linings of the upper airways, lips, mouth, salivary glands, throat and larynx (head and neck SCC, HNSCC). Cutaneous SCC is the second most common non-melanoma skin cancer—and most of them are eradicated by surgical excision, a subset of these tumors become highly aggressive and show higher recurrence and metastatic rates, causing the death of patients [1]. HNSCCs had an incidence of more than 700,000 cases worldwide in 2018, with 42–56% mortality [2]. The main risk factors for cutaneous SCC are exposure to sunlight and immunosuppression.
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