Abstract
CD44v6-containing isoforms are frequently de novo expressed in gastric cancer (GC). Whether CD44v6 has a central role in GC transformation and/or progression, whether it conditions response to therapy or whether it is only a bystander marker is still not known. Therefore, we aimed to clarify the role of CD44v6 in GC. We generated GC isogenic cell lines stably expressing CD44s or CD44v6 and tested them for different cancer hallmarks and response to cisplatin, and we further confirmed our findings in cells that endogenously express CD44v6. No correlation between overexpression of CD44v6 and the tested cancer hallmarks was observed, suggesting CD44v6 is not a driver of GC progression. Upon cisplatin treatment, CD44v6+ cells survive better and have lower apoptosis levels than CD44v6− cells, possibly due to concomitant activation of STAT3 and P38. In co-culture experiments, we discovered that CD44v6+ cells are involved in GC cell overgrowth after cisplatin treatment. In conclusion, we show that CD44v6 expression increases cell survival in response to cisplatin treatment in GC cells and that these cells override CD44v6-negative cells after cisplatin-treatment. This suggests that tumor expression of CD44v6-containing variants may condition the outcome of GC patients treated with chemotherapy.
Highlights
CD44 isoform (CD44s) is a ubiquitous membrane receptor that was first described for its role as an organ-specific, lymphocyte homing, cell surface molecule [1]
In an attempt to clarify the role of CD44v6 overexpression in gastric cancer (GC), we generated isogenic cell lines by stably expressing in a CD44-null MKN74 GC cell line (Figure S1), the following sequences: (i) a CD44v6-containing isoform highly expressed in GC cells (GP202 cell line, Figure S2) [12], on mentioned as MKN74_CD44v6 cells (Figure 1A); (ii) the CD44s isoform (MKN74_CD44s cells, Figure 1A), or; (iii) the empty plasmid (MKN74_Mock cells, Figure 1A)
Non-stimulated isogenic cell lines presented no differences regarding the expression of known CD44 interactors and downstream signaling partners (AKT, EGFR, ERK 1/2, P38 and STAT3, and respective phosphorylated forms) at the post-translational level (Figure 2E,F)
Summary
CD44 is a ubiquitous membrane receptor that was first described for its role as an organ-specific, lymphocyte homing, cell surface molecule [1]. It has since been associated with a large number of key cellular adhesion processes, such as homotypic and heterotypic cellular adhesion [2,3]. CD44 has been described as a co-receptor with a pivotal role in intracellular signaling, mediating key aspects of cellular behavior such as motility and cell survival [7,8,9]. The standard CD44 isoform (CD44s) includes only the constitutive exons, while the variant isoforms (CD44v) contain one or more variable exons (in addition to the constitutive ones) [7,9,10,11]
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