SHROOM2 inhibits tumor metastasis through RhoA–ROCK pathway-dependent and -independent mechanisms in nasopharyngeal carcinoma

Abstract

SHROOM2 is a key mediator of RhoA–ROCK pathway that regulates cell motility and actin cytoskeleton organization. However, the functions of SHROOM2 beyond RhoA/ROCK signaling remain poorly understood. Here, we report that SHROOM2 not only participates in RhoA–ROCK-induced stress fiber formation and focal adhesion, but also had an unanticipated role in suppressing epithelial-to-mesenchymal transition (EMT) and tumor metastasis. Depletion of SHROOM2 in nasopharyngeal carcinoma (NPC) cells enhances mesenchymal characteristics and reduces epithelial markers, concomitant with increased motility, enabling the development of invasion and tumor metastasis, which are largely ROCK-independent, as ROCK inhibitor Y-27632 did not cause EMT phenotype; furthermore, combination of ROCK inhibition and SHROOM2 depletion resulted in the most robust increases in cell migration and invasion, indicating that SHROOM2 and ROCK work synergistically rather than epistatic. Analysis of clinical samples suggested that SHROOM2 is downregulated in NPC and the expression of SHROOM2 in metastatic NPC was even lower than in the primary tumors. Our findings uncover a non-canonical role of SHROOM2 as a potent antagonist for EMT and NPC metastasis.

An early cell shape transition drives evolutionary expansion of the human forebrain

“…Our findings also support a link between ZEB2 and cytoskeletal targets, and although the specific nature of this link remains to be elucidated, several reports have shown cross-regulation between ZEB2 and the actin cytoskeleton (Wiles et al, 2013;Yuan et al, 2019).…”

Differential Expression and Alternative Splicing of Transcripts Associated With Cisplatin-Induced Chemoresistance in Nasopharyngeal Carcinoma

“…The correlation between these pathway and tumor progression, including NPC, has been proven in previous studies. Especially, focal adhesion (Liu et al, 2018;Yuan et al, 2019;Yu et al, 2019), apoptosis (Li M. et al, 2019;Liang et al, 2019;Wang et al, 2019;Xie et al, 2019), and the tumor necrosis factor (TNF) signaling pathway (Lu et al, 2011;Ou et al, 2015;Huang et al, 2017;Deng et al, 2018) have been reported to be closely related to NPC development.…”

Multicellular contractility contributes to the emergence of mesothelioma nodules

“…Previous investigations particularly in non-tumorous cells described an IC50 lower than 2µ M for both blebbistatin and Y27632 26,41 . However, several recent preclinical studies in different tumor entities used significantly higher concentrations of those inhibitors to achieve meaningful effects [42][43][44][45] . Furthermore, the concept of multicellular resistance suggests that tumor cells are more resistant to drugs when they are part of multicellular aggerates, presumably due to limited intake within the bulk of the 3D structure [46][47][48] .…”