Abstract
CD44 is a transmembrane glycoprotein, the phosphorylation of which can directly trigger intracellular signaling, particularly Akt protein, for supporting cell growth, motility and invasion. This study examined the role of CD44 on the progression of Cholangiocarcinoma (CCA) using metabolic profiling to investigate the molecular mechanisms involved in the Akt signaling pathway. Our results show that the silencing of CD44 decreases Akt and mTOR phosphorylation resulting in p21 and Bax accumulation and Bcl-2 suppression that reduces cell proliferation. Moreover, an inhibition of cell migration and invasion regulated by CD44. Similarly, the silencing of CD44 showed an alteration in the epithelial-mesenchymal transition (EMT), e.g. an upregulation of E-cadherin and a downregulation of vimentin, and the reduction of the matrix metalloproteinase (MMP)-9 signal. Interestingly, a depletion of CD44 leads to metabolic pathway changes resulting in redox status modification and Trolox (anti-oxidant) led to the recovery of the cancer cell functions. Based on our findings, the regulation of CCA progression and metastasis via the redox status-related Akt signaling pathway depends on the alteration of metabolic profiling synchronized by CD44.
Highlights
To study the function of Cluster of differentiation 44 (CD44) on CCA cells, we carried out stable knockdown of CD44 and examined cell proliferation, migration and invasion
Stable knockdown in KKU-213 and KKU-156 CCA cell lines was performed using CD44shRNA to target two different sequences allowing the exploration of cellular functions including cell proliferation
Our work shows that the depletion of CD44 affected cell invasion via the reduction of the matrix metalloproteinases (MMP)-9 signal, which is a family of zinc-dependent endopeptidases with important functions in extracellular matrix remodeling during development, and in inflammation and wound repair processes [51, 52]
Summary
Cholangiocarcinoma Cluster of differentiation 44 (CD44) is a family of transmembrane glycoproteins containing extracellular transmembrane and intracellular cytoplasmic domains [1]. Members of this family are alternatively spliced into several variant exon products of the extracellular domains as variant isoforms [2]. CD44 can be used as a cell surface marker in order to identify cancer stem-like cells (CSCs) in many cancer types [3,4,5,6].
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