HSP27 associates with epithelial–mesenchymal transition, stemness and radioresistance of salivary adenoid cystic carcinoma

Abstract

Epithelial–mesenchymal transition (EMT) has been shown to associate with cancer stem cells and radioresistance. However, it is obscure whether EMT itself or specific EMT regulators play causal roles in these properties of salivary adenoid cystic carcinoma (SACC). Here, we exhibited that overexpression of HSP27 drove the migration and invasion, induced EMT, as well as mediated TGF‐β1‐induced EMT in SACC cells, accompanying the up‐regulation of Snail1 and Prrx1. Conversely, HSP27 silencing reduced the migration and invasion and contributed to MET of SACC cells. HSP27 indirectly down‐regulates the expression of E‐cadherin through activating Snail1 and Prrx1 expressions. Overexpression of Snail1 or Prrx1 restored the migration and invasion in HSP27 knockdown cells. Enforced expression of HSP27 enhanced colony formation, CD133+/CD44+ population and radioresistance of SACC cell lines. In addition, HSP27 expression was positively associated with radioresistance and poor prognosis of SACC patients as well as with the expression of Prrx1 or Snail1 in SACC tissues. The data confirm an important function for HSP27 in SACC progression through regulating EMT and stemness, and they imply the possible association between EMT and radioresistance of SACC.

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…These HSP27-associated mechanisms of EMT were similar in some cases of cancer while different in others. So, the significance of HSP27 for TGF-β1-induced EMT was demonstrated in four distinct types of carcinomas [138,141,144,145]. Notably, diverse HSP27-involving mechanisms were described for different inducers of EMT.…”

“…First indications about a link between HSP27 and cancer stemness appeared in 2010: The small chaperone was shown to be involved in TGF-β1-induced EMT in lung cancer cells (A549 cell line) and this involvement was independent of Smad [138]. Then, the contribution of HSP27 to EMT was found in several different cancer-related studies and models, including breast cancer [139], gastric cancer [140,141], prostate cancer [142,143], renal cell carcinoma [144], and salivary adenoid cystic carcinoma [145]. These HSP27-associated mechanisms of EMT were similar in some cases of cancer while different in others.…”

“…Notably, diverse HSP27-involving mechanisms were described for different inducers of EMT. For example, the HSP27-mediated upregulation of Snail and Prrx1 seemed to promote TGF-β1-induced EMT in salivary adenoid cystic carcinoma [145]. In the case of IL-6-induced EMT in prostate cancer, silencing HSP27 reversed the phenotypic transition by impairing MMP activity, cell migration, and invasion [142].…”

“…In a similar model with breast cancer, HSP27 was found to be responsible for vasculogenic mimicry activity in populations of mammosphere-forming CD24(−)CD44(+)ALDH(+) CSCs [152]; the activity's manifestation was mediated by the EGF-triggered signaling pathway, resulting in HSP27 phosphorylation. By means of silencing HSP27 and its overexpression in salivary adenoid cystic carcinoma cell lines, it was shown that HSP27 increases CSC-like (CD133+/CD44+) cells exhibiting radioresistance, reduced E-cadherin levels, and the enhanced capacity for cell migration and invasion; all these effects were due to the HSP27-mediated upregulation of Snail1 and Prrx1 expression [145]. HSP27-associated resistance to apoptosis, oxidative stress, and some chemotherapeutic agents was reported for lung CSCs [148,153], oral CSC-like cells [147], colon CSCs [154], and esophageal CSCs [155].…”

Disparities in Head and Neck Cancer: A Case for Chemoprevention with Vitamin D

“…Vitamin D down-regulated Heat shock protein beta-1 (HSP27), a multi-functional protein with well documented roles in HNC inflammation, proliferation, cancer progression, stemness, EMT, and more recently radio-sensitization and therapeutic resistance [21,[112][113][114][115][116][117]. Moreover, in SCC of the tongue HSP27 inhibition represses apoptosis and enhances sensitivity to chemotherapies [21] supporting a role for agents that reduce or impair HSP27.…”