Abstract
The homeobox-containing gene HOXB7 plays an important role in the pathogenesis and progression of many cancers, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study comprehensively analyzed the expression and clinical significance of HOXB7 in HCC and explored its potential mechanism in tumor progression. We found HOXB7 was highly expressed in HCC cell lines with highly metastatic potential and cancerous tissues from patients with tumor recurrence. The abilities of proliferation, migration, and invasion were notably decreased by depletion of HOXB7, and were enhanced by its enforced expression in vitro. HOXB7 expression was positively correlated with tumor progression and lung metastasis in vivo. The gene microarray data implied that HOXB7 affects biological functions of HCC cells through MAPK/ERK pathway activation. Further study confirmed that the effect of HOXB7 in activating MAPK/ERK pathway via induction of basic fibroblast growth factor (bFGF) secretion, and the inhibition of bFGF secretion could abolish MAPK/ERK pathway activation after ectopic expression of HOXB7. Chromatin immunoprecipitation experiments and luciferase reporter assays confirmed that HOXB7 promoted bFGF secretion via binding its promoter directly. Furthermore, the clinical significance of HOXB7 expression was confirmed using tissue microarrays containing 394 HCC tissue specimens. Patients with high HOXB7 expression showed shorter survival times and higher recurrence rates, and HOXB7 was an independent indicator for survival and recurrence. Overall, HOXB7 promotes HCC cell proliferation, migration, and invasion through the bFGF-induced MAPK/ERK pathway activation. It might be a novel prognostic factor in HCC and a promising therapeutic target for tumor metastasis and recurrence.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide [1]
We demonstrated that HOXB7 enhances proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells through bFGFinduced MAPK/ERK pathway activation, and its expression was strongly associated with tumor recurrence and poor prognosis of HCC patients after surgery
Immunocytochemical analysis showed that HOXB7 protein was expressed predominantly in the nuclei of high metastatic potential HCC cells (MHCC97H and HCCLM3 cells) (Figure 1C), and the staining intensity was consistent with qRT-PCR and western blot results
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide [1]. longterm survival of HCC patients has been obtained in some clinical centers, the prognosis of HCC patients is still dismal due to the rapid progression of this disease [2]. Further studies indicated that HOXB7 induces epithelial mesenchymal transition (EMT), [9] transactivates pathways involving Ras/ Rho, [9] PI3K/AKT, and MAPK [8]. These results suggest that HOXB7 plays an important role in tumor development and progression. Only one study revealed HOXB7 expression was significantly higher in HCC tissues, and it was an independent prognosis factor for OS [14], but the mechanism of HOXB7 involvement in HCC progress has not been elucidated
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