Loss Of Acvrib Leads To Increased Squamous Cell Carcinoma Aggressiveness Through Alterations In Cell-Cell And Cell-Matrix Adhesion Proteins

Keywords

Activin A; Adhesion; Cytoskeleton dynamics; Squamous cell carcinoma; Three-dimensional culture

Abstract

Squamous cell carcinomas of the head and neck (HNSCC) and esophagus (ESCC) pose a global public health issue due to high mortality rates. Unfortunately, little progress has been made in improving patient outcomes. This is partially a result of a lack of understanding the mechanisms that drive SCC progression. Recently, Activin A signaling has been implicated in a number of cancers, yet the role of this pathway in SCC remains poorly understood. We have previously discovered that the Activin A ligand acts as a tumor suppressor when epithelial Activin receptor type IB (ACVRIB) is intact; however, this effect is lost upon ACVRIB downregulation. In the present study, we investigated the function of ACVRIB in the regulation of SCC. Using CRISPR/Cas9-mediated ACVRIB-knockout and knockdown using siRNA, we found an increased capacity to proliferate, migrate, and invade upon ACRIB loss, as ACVRIB-KO cells exhibited an altered cytoskeleton and aberrant expression of E-cadherin and integrins. Based on chemical inhibitor studies, our data suggests that these effects are mediated through ACVRIB-independent signaling via downstream activation of Smad1/5/8 and MEK/ERK. Overall, we present a novel mechanism of SCC progression upon ACVRIB loss by showing that Activin A can transduce a signal in the absence of ACVRIB.

Publication Date

1-1-2017

Publication Title

American Journal of Cancer Research

Volume

7

Issue

12

Number of Pages

2422-2437

Document Type

Article

Personal Identifier

scopus

Socpus ID

85039072075 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85039072075

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