EB2 promotes hepatocellular carcinoma proliferation and metastasis via MAPK/ERK pathway by modulating microtubule dynamics

Abstract

Metastasis is the main cause of poor postoperative survival of hepatocellular carcinoma (HCC) patients. Cytoskeleton rearrangement is a key event in cancer metastasis. However, the significance of microtubule (MT), one of the core components of cytoskeleton, in this process is only beginning to be revealed. Here, we found that end-binding protein 2 (EB2), a MT dynamics regulator, is highly expressed in HCC and predicts poor prognosis of HCC patients. Functional studies show that EB2 overexpression promotes HCC proliferation, invasion and metastasis in vitro and in vivo, while EB2 knockdown has opposite results. Mechanistically, EB2 mediates MTs destabilization, increases Src activity, and thus facilitates extracellular signal-regulated kinase (ERK) signaling activation, which could in turn promotes EB2 expression in HCC, eventually resulting in enhanced HCC proliferation, invasion and metastasis. Furthermore, U0126, a specific ERK inhibitor, could effectively inhibit EB2-mediated HCC proliferation and metastasis in vitro and in vivo. In conclusion, EB2 coordinates MT cytoskeleton and intracellular signal transduction, forming an EB2-MT-ERK positive feedback loop, to facilitate HCC proliferation, invasion and metastasis. EB2 could serve as a promising prognostic biomarker and potential therapeutic target for HCC; HCC patients with high EB2 expression may benefit from treatment with ERK inhibitors.

Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-κB downregulation

“…The disruption of microtubule dynamics has been shown to lead to activation of ERK and cell death in earlier studies, such as in hepatocellular carcinoma cell lines, in which end-binding protein 2 was shown to decrease microtubule stability, which then led to ERK activation via activation of Src kinase, part of the focal adhesion complex (Zhong et al 2021). Tien and Chang (2014) demonstrated a link between pERK levels and another member of focal adhesions, RhoA, which stabilises microtubules.…”

Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis

“…Our results showed that Notch4 silencing downregulated phosphorylation of ERK, JNK, and P38. Meanwhile, Notch4 overexpression increased ERK, JNK, and P38 phosphorylation in A549 and H1299 cells, which was partly abrogated by the specific inhibitors U0126 ( Zhong et al, 2021 ), SP600125 ( Zhang et al, 2021 ), and SB203580 ( Kwak et al, 2021 ). Notably, the increased cell proliferation and migration and inhibited cell apoptosis induced by Notch4 overexpression in A549 and H1299 cells were prevented by the co-administration of U0126, SP600125, or SB203580.…”

Scoparone inhibits the growth of liver cancer cells by regulating MAPK signaling pathway

“…For example, PNO1 mediated the autophagy and apoptosis of liver cancer via this pathway [20]. EB2 also promoted liver cancer proliferation and metastasis via MAPK pathway by regulating microtubule dynamics [21]. Therefore, this pathway might also act as a therapeutic target for liver cancer therapy.…”