Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma

Hsin-An Chen, Tsang Chih Kuo, Chi Feng Tseng, Jui Ti Ma, Shu Ting Yang, Chia Jui Yen, Ching Yao Yang, Shian-Ying Sung, Jen Liang Su

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Angiopoietin-like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial-mesenchymal transition (EMT)-driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)-dependent early growth response protein 1 (Egr-1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients. Conclusion: ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor−AKT/ERK−Egr-1−Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637-1651).

Original languageEnglish
Pages (from-to)1637-1651
Number of pages15
JournalHepatology
Volume64
Issue number5
DOIs
Publication statusPublished - Nov 1 2016

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Angiopoietins
Hepatocellular Carcinoma
Gastropoda
Neoplasms
Proteins
Epithelial-Mesenchymal Transition
Early Growth Response Protein 1
Proto-Oncogene Proteins c-akt
Neoplastic Stem Cells
sorafenib
Gastroenterology
Phosphotransferases
Neoplasm Metastasis

ASJC Scopus subject areas

  • Hepatology

Cite this

Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma. / Chen, Hsin-An; Kuo, Tsang Chih; Tseng, Chi Feng; Ma, Jui Ti; Yang, Shu Ting; Yen, Chia Jui; Yang, Ching Yao; Sung, Shian-Ying; Su, Jen Liang.

In: Hepatology, Vol. 64, No. 5, 01.11.2016, p. 1637-1651.

Research output: Contribution to journalArticle

Chen, Hsin-An ; Kuo, Tsang Chih ; Tseng, Chi Feng ; Ma, Jui Ti ; Yang, Shu Ting ; Yen, Chia Jui ; Yang, Ching Yao ; Sung, Shian-Ying ; Su, Jen Liang. / Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma. In: Hepatology. 2016 ; Vol. 64, No. 5. pp. 1637-1651.
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