Introduction
Hepatocellular carcinoma (HCC) is a well-known deadly malignancy, accounting for about 8.2% cancer-related death worldwide. Particularly, invasion and metastasis is still the main obstacle to improve the survival of advanced HCC patients. Although high-throughout screen, such as GWAS, whole exon-sequencing, RNA sequencing has uncovered some genetics changes, the driver genes are relatively low mutation ratio in HCC. On the other hand, accumulated evidence suggests that cancer cells can use the similar regulation mechanisms in mammalian development. Our previous work revealed that goosecoid, which plays critical roles in gastrulation and neural crest development could promote the metastasis of HCC by modulating the epithelial-mesenchymal transition. However, the underlying development-related mechanisms utilized by HCC cells remain largely unknown, particularly genes involving epigenetic changes.
Aims & Methods
Aims: Polycomb proteins, such as EZH2 and EED, have been widely revealed involving in development and cancer. However, the roles of another development-related polycomb protein suppressor of zeste 12 (SUZ12) in cancer remains largely unknown. Here, we investigated the roles of SUZ12 in hepatocellular carcinoma (HCC) and the underlyling mechanisms.
Methods: Tissue microarray based on 88 tumor tissues and 27 normal liver tissues was used to examine the expression level of SUZ12. The gain- and loss- of function analysis was conducted to evaluate the effects of SUZ12 on the proliferation, migration and invasion of HCC cells. Meanwhile, luciferase reporter assay and RT-PCR assay were conducted to examine the effect of SUZ12 on the transcriptional activity of chemokine receptors 7 (CXCR7).
Results
High frequency of 17q amplification including SUZ12 locus in HCC was revealed through genome sequencing. Further, SUZ12 expressed relatively higher in tumor tissues and HCC cell lines, particularly in HCC cells with highly metastatic potential. Clinically, high SUZ12 expression was an independent prognostic factor for poor overall survival (hazard ratio =2.540, p = 0.002) of HCC patients, which was further confirmed by analyses of TCGA based database. Functionally, in vitro assays revealed that up-regulation of SUZ12 promoted the migration and invasion of HCC cells, whereas down-regulation of SUZ12 inhibited the migration and invasion potentials. Furthermore, we found SUZ12 strongly upregulated the transcriptional level of CXCR7 screened from chemokine receptors family. Also, CXCR7 was revealed to contribute to the tumor-promoting roles of SUZ12. Of interest, luciferase reporter assay revealed SUZ12 positively controlled the CXCR7 via direct promoter combination but not epigenetic suppression. Moreover, high SUZ12 expression was positively correlated with CXCR7 in advanced patients with portal vein invasion.
Conclusion
These findings indicate that SUZ12 is associated with the poor survival of HCC, and promotes the invasion potential of HCC cells partially by activating CXCR7 transcription. This non-classical transcriptional control of SUZ12 in HCC warrants future exploration.
References
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Disclosure
The authors have no conflict of interest.
