Basic leucine zipper and W2 domain 2 (BZW2), also known as 5MP1, is a protein related to translation regulation. Evidence from previous studies indicates that BZW2 is involved in tumorigenesis in several cancers. However, little is known about the role of BZW2 in hepatocellular carcinoma (HCC). In this study, we first analyzed the gene expression profile of BZW2 in multiple HCC datasets. Next, we explored the biological effects of BZW2 in HCC cell lines. BZW2 was overexpressed in different HCC cohorts. Multivariate analysis confirmed that increased BZW2 expression is an independent prognostic indicator of shorter overall survival. BZW2 coexpressed genes were mainly enriched in the biological processes of ribonucleoprotein complex biogenesis, rRNA metabolism, translational initiation, and negative regulation of metabolic processes. BZW2 depletion reduced proliferation, clonality, and invasion and increased apoptosis in MHCC97-H cells. Furthermore, BZW2 overexpression or knockdown enhanced or impaired c-Myc expression, respectively. Overall, these findings identified BZW2 as a biomarker of HCC and provided novel insight that the effect of BZW2 on the translatome is a potential mechanism that promotes HCC progression via the c-Myc pathway.
Background and Aims
Great efforts have been made towards increasing our understanding of the pathogenesis involved in hepatocellular carcinoma (HCC), but the rapid growth inherent to such tumor development remains to be explored.
Methods
We identified distinct gene coexpression modes upon liver tumor growth using weighted gene coexpression network analysis. Modeling of tumor growth as signaling activity was employed to understand the main cascades responsible for the growth. Hub genes in the modules were determined, examined
in vitro
, and further assembled into the growth signature.
Results
We revealed modules related to the different growth states in HCC, especially the fastest growth module, which is preserved among different HCC cohorts. Moreover, signaling flux in the cell cycle pathway was found to act as a driving force for rapid growth. Twenty hub genes in the module were identified and assembled into the growth signature, and two genes (
NCAPH
, and
RAD54L
) were tested for their growth potential
in vitro
. Genetic alteration of the growth signature affected the global gene expression. The activity of the signature was associated with tumor metabolism and immunity in HCC. Finally, the prognosis effect of the growth signature was reproduced in nine cancers.
Conclusions
These results collectively demonstrate the molecule organization of rapid tumor growth in HCC, which is a highly synergistic process, with implications for the future management of patients.
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