Maelstrom Promotes Hepatocellular Carcinoma Metastasis by Inducing Epithelial-Mesenchymal Transition by Way of Akt/GSK-3β/Snail Signaling

• DOI: 10.1002/hep.26677
• Publication Date: 2013-08-08T15:21:44Z
• Authors: Lulu Liu; Yongdong Dai; Jinna Chen; Tingting Zeng; Yan Li; Leilei Chen; Ying-Hui Zhu; Jiangchao Li; Stephanie Ma; Dan Xie; Yun-Fei Yuan; Xin-Yuan Guan
• Keywords: Male; cell migration; gene amplification; epithelial mesenchymal transition; transcription factor Snail; transcription factor NANOG; chromosome 1q; gene silencing; Glycogen Synthase Kinase 3; Mice; BMI1 protein; vimentin; Cell Movement; carcinogenicity; cell growth; CD133 antigen; Neoplasm Metastasis; cancer resistance; cancer survival; Hermes antigen; Liver Neoplasms - physiopathology; endoglin; Notch1 receptor; 0303 health sciences; messenger RNA; adult; Liver Neoplasms; article; glycogen synthase kinase 3beta; Middle Aged; enzyme activity; 3. Good health; DNA-Binding Proteins; chemosensitivity; female; activated leukocyte cell adhesion molecule; Carrier Proteins - genetics - physiology; beta catenin; Disease Progression; Female; membrane antigen; carcinogenesis; CD24 antigen; octamer transcription factor 4; cancer stem cell; liver cell carcinoma; Carcinoma, Hepatocellular; Epithelial-Mesenchymal Transition; cell surface marker; gene overexpression; animal experiment; 610; cell motility; In Vitro Techniques; uvomorulin; animal tissue; Glycogen Synthase Kinase 3 - physiology; 03 medical and health sciences; Hepatocellular - physiopathology; fibronectin; Epithelial-Mesenchymal Transition - physiology; alpha catenin; 617; short hairpin RNA; Animals; Humans; controlled study; human; cell renewal; Cell Proliferation; Glycogen Synthase Kinase 3 beta; animal model; human cell; Carcinoma; Maelstrom gene; human tissue; Carcinoma, Hepatocellular - physiopathology; Disease Models, Animal; cancer recurrence; protein kinase B; Carrier Proteins; Proto-Oncogene Proteins c-akt

Amplification of 1q is one of the most frequent chromosomal alterations in human hepatocellular carcinoma (HCC). In this study we identified and characterized a novel oncogene, Maelstrom (

MAEL

), at 1q24. Amplification and overexpression of

MAEL

was frequently detected in HCCs and significantly associated with HCC recurrence (

P

= 0.031) and poor outcome (

P

= 0.001). Functional study demonstrated that

MAEL

promoted cell growth, cell migration, and tumor formation in nude mice, all of which were effectively inhibited when

MAEL

was silenced with short hairpin RNA (shRNAs). Further study found that MAEL enhanced AKT activity with subsequent GSK-3β phosphorylation and Snail stabilization, finally inducing epithelial-mesenchymal transition (EMT) and promoting tumor invasion and metastasis. In addition,

MAEL

up-regulated various stemness-related genes, multidrug resistance genes, and cancer stem cell (CSC) surface markers at the messenger RNA (mRNA) level. Functional study demonstrated that overexpression of

MAEL

increased self-renewal, chemoresistance, and tumor metastasis.

Conclusion

:

MAEL

is an oncogene that plays an important role in the development and progression of HCC by inducing EMT and enhancing the stemness of HCC. (Hepatology 2014;59:531–543)