Journal
CANCER LETTERS
Volume 506, Issue -, Pages 128-141Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.03.001
Keywords
Cytoskeleton; EMT; Metastasis; Early recurrence; Prognosis
Categories
Funding
- National Science and Technology Major Project [2017ZX10203207-002-003]
- National Natural Science Foundation of China [81773139, 81272395, 81172018]
- Key Project of National Nature Science Foundation of China [81330057]
- National Key R&D Program of China [2016YFC0902400]
- Key Project of Science & Technology Plan of Science & Technology Department of Hunan Province [2014CK2003]
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Metastasis is a major challenge in improving survival for HCC patients, with EMT playing a critical role. STMN2, a regulator of MT dynamics, is up-regulated in HCC and correlates with aggressive clinicopathological features and poor prognosis. STMN2 orchestrates MT disassembly to facilitate EMT via TGF-beta signaling, providing new insights into cancer metastasis mechanisms.
Metastasis remains the major obstacle of improving the survival of patients with hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is critical to cancer metastasis. Successful induction of EMT requires dramatic cytoskeleton rearrangement. However, the significance of microtubule (MT), one of the core components of cell cytoskeleton, in this process remains largely unknown. Here we revealed that STMN2, an important MT dynamics regulator, is barely expressed in normal live tissues but markedly up-regulated in HCCs, especially in those with early recurrence. High STMN2 expression correlates with aggressive clinicopathological features and predicts poor prognosis of HCC patients. STMN2 overexpression in HCC cells promotes EMT, invasion and metastasis in vitro and in vivo, whereas STMN2 knockdown has opposite results. Mechanistically, STMN2 modulates MTs disassembly, disrupts MT-Smad complex, and facilitates release from MT network, phosphorylation and nuclear translocation of Smad2/3 even independent of TGF beta stimulation, thereby enhancing TGF beta signaling. Collectively, STMN2 orchestrates MT disassembly to facilitate EMT via TGF-beta signaling, providing a novel insight into the mechanisms underlying cancer metastasis. STMN2 is a promising prognostic biomarker and potential therapeutic target for HCC.
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