Abstract
Cell contact inhibition (CCI) is deregulated in cancer. Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. We found that dual-specificity phosphatase 10 (DUSP10) is involved in CRC. DUSP10 overexpression increased the growth of CRC cell lines and mouse xenografts, while the opposite phenotype was observed by DUSP10 silencing. High cell density (HD) induced DUSP10 expression in CRC cell lines, particularly within the nucleus. Yes-associated protein 1 (YAP1) is activated by dephosphorylation, controlling organ growth and CCI, both processes being deregulated in CRC. Expression levels and localization of DUSP10 matched with YAP1 levels in CRC cell lines. DUSP10 and YAP1 co-immunoprecipitated and their interaction was dependent on YAP1 Ser397. The existence of DUSP10 and YAP1 pathway in vivo was confirmed by using a transgenic Drosophila model. Finally, in CRC patients’ samples, high levels of nuclear DUSP10 correlated with nuclear YAP1 in epithelial tumor tissue. Strong nuclear DUSP10 staining also correlated with high tumor stage and poor survival. Overall, these findings describe a DUSP10–YAP1 molecular link in CRC cell lines promoting cell growth in HD. We present evidence suggesting a pro-tumorigenic role of nuclear DUSP10 expression in CRC patients.
Highlights
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide; more than 600,000 people die annually [1]
HT29lucD6-shDUSP10 had the opposite effect on p-p38, while p-jun N-terminal kinase (JNK) did not change (Figure S1d)
These results confirmed the efficiency of our cell model in vitro and showed that dual-specificity phosphatase 10 (DUSP10) modulates p38 but not JNK in CRC cells
Summary
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide; more than 600,000 people die annually [1]. New treatments have been developed for primary and metastatic CRC, but cure rates and long-term survival have changed little in the past several decades [2]. Statistics indicate that currently available treatment options do not achieve the desired efficiency, requiring the development of new therapeutic strategies in CRC disease [3]. Cell contact inhibition (CCI) regulates cell proliferation and maintains cellular density in tissues. CCI is deregulated in cancer and represents a fundamental distinction between cancerous and normal cells [4]. The Hippo signaling is an evolutionarily conserved pathway implicated in the control of organ size, and its downregulation promotes tumorigenesis [5]. A major downstream effector of this pathway
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