Abstract
Invadopodia are actin-enriched membrane protrusions that are important for extracellular matrix degradation and invasive cell motility. Src homolog domain-containing phosphatase 2 (SHP2), a non-receptor protein tyrosine phosphatase, has been shown to play an important role in promoting cancer metastasis, but the underlying mechanism is unclear. In this study, we found that depletion of SHP2 by short-hairpin RNA suppressed invadopodia formation in several cancer cell lines, particularly in the SAS head and neck squamous cell line. In contrast, overexpression of SHP2 promoted invadopodia formation in the CAL27 head and neck squamous cell line, which expresses low levels of endogenous SHP2. The depletion of SHP2 in SAS cells significantly decreased their invasive motility. The suppression of invadopodia formation by SHP2 depletion was restored by the Clostridium botulinum C3 exoenzyme (a Rho GTPase inhibitor) or Y27632 (a specific inhibitor for Rho-associated kinase). Together, our results suggest that SHP2 may promote invadopodia formation through inhibition of Rho signaling in cancer cells.
Highlights
Invadopodia are F-actin-enriched membrane pro trusions that localize at the ventral surface of cells and function in extracellular matrix degradation during cancer invasion and metastasis [1]
Our results indicate that Src homolog domaincontaining phosphatase 2 (SHP2) promotes invadopodia formation and cell invasion through inhibition of Rho signaling in head and neck squamous cell carcinomas (HNSCC)
We show that SHP2 is important for invadopodia formation in several types of cancer cell lines, HNSCC cells
Summary
Invadopodia are F-actin-enriched membrane pro trusions that localize at the ventral surface of cells and function in extracellular matrix degradation during cancer invasion and metastasis [1]. The results showed that this increased expression of SHP2 promoted the formation of invadopodia in CAL27 cells (Figure 3D) and their capability to degrade matrix proteins (Figure 3E) These data together indicate that SHP2 plays a positive role in invadopodia formation and matrix degradation of HNSCC cells. Our results show that the depletion of SHP2 suppressed ~50% of invadopodia formation and matrix degradation in SAS cells (Figure 2), but ~90% of the capability for Matrigel invasion (Figure 4A) These data suggest that other cellular activities important for cell invasion may be regulated by SHP2 as well. The expression and activation of ERK was not affected by SHP2 in SAS or CAL27 cells (Supplementary Figure S2A and S2B) Invadopodia formation in both cell lines was not altered by the specific MEK inhibitor PD98059 (Supplementary Figure S2C and S2D). Inhibition of ROCK by Y27632 significantly increased the formation of invadopodia in CAL27 cells (Figure 5F and 5G), indicating that suppression of ROCK is beneficial to invadopodia formation in the cancer cells with low expression levels of SHP2
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