Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand.
Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
PLoS One. 2021 Mar 29;16(3):e0245871. doi: 10.1371/journal.pone.0245871. eCollection 2021.
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.
CD44 是一种跨膜糖蛋白，其磷酸化可直接触发细胞内信号转导，特别是 Akt 蛋白，从而支持细胞生长、运动和侵袭。本研究使用代谢组学来研究 Akt 信号通路中涉及的分子机制，探讨了 CD44 对胆管癌 (CCA) 进展的作用。我们的结果表明，沉默 CD44 可降低 Akt 和 mTOR 磷酸化，导致 p21 和 Bax 积累，Bcl-2 抑制减少细胞增殖。此外，CD44 还可抑制细胞迁移和侵袭。同样，沉默 CD44 也会导致上皮-间充质转化 (EMT) 的改变，例如 E-钙黏蛋白上调和波形蛋白下调，以及基质金属蛋白酶 (MMP)-9 信号减少。有趣的是，CD44 的耗竭会导致代谢途径的改变，从而导致氧化还原状态的改变，而 Trolox（抗氧化剂）则可恢复癌细胞的功能。基于我们的发现，通过与氧化还原状态相关的 Akt 信号通路调节 CCA 的进展和转移，取决于 CD44 同步改变代谢谱。
