Abstract
BackgroundThe role of hypoxia-inducible factor-1α (HIF-1α) in primary colorectal cancer (CRC) and colorectal liver metastasis (CRLM) has remained unclear. The aim of this study was to investigate HIF-1α expression and its association with prognosis in patients with CRLM with a focus on hepatic stellate cells (HSCs).MethodsColon cancer cells were cultured in HSC-conditioned medium (CM), and HIF-1α expression and cell migration were analyzed. Seventy-five patients with CRLM who underwent an initial curative hepatectomy were enrolled. We examined HIF-1α expressions and patient prognosis between primary CRCs and the matched liver metastatic specimens.ResultsActivated HSCs induced HIF-1α mRNA and protein expression in colon cancer cells (p < 0.01) and promoted cell migration (p < 0.01). The positive rates of HIF-1α expression in primary CRCs and liver metastases were 68.0 and 72.0%, respectively. There were no differences in overall (OS) and disease-free survival (DFS) of HIF-1α expression in primary CRC. However, HIF-1α expression in liver metastasis correlated to poor prognosis in both OS and DFS. Furthermore, patients with HIF-1α positive expression in liver metastasis had poor prognosis.ConclusionHIF-1α expression in liver metastasis determines poor prognosis of CRLM patients. HSCs might play a key role in aggressive phenotypes of tumor cells.
Highlights
The role of hypoxia-inducible factor-1α (HIF-1α) in primary colorectal cancer (CRC) and colorectal liver metastasis (CRLM) has remained unclear
Tumor malignancy is enhanced in the liver by Hepatic stellate cell (HSC) We first examined the impact of HSC-conditioned medium (CM) on HIF-1α expression in HCT116 colorectal cancer cells
We found that HSCs conditioned medium (HSC-CM) induced both HIF-1α mRNA and protein expression in HCT116 cells (p < 0.01) (Fig. 2a, b)
Summary
The role of hypoxia-inducible factor-1α (HIF-1α) in primary colorectal cancer (CRC) and colorectal liver metastasis (CRLM) has remained unclear. In patients with colorectal liver metastasis (CRLM), surgical resection improves patient prognosis and is recommended if the resection will be curative [1,2,3,4,5]. With the implementation of “targeted” molecular therapies against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), the median overall survival (OS) of patients with metastatic colorectal cancer (CRC) has progressively improved, surpassing 30 months [6,7,8]. Previous studies reported that while the immune microenvironment in the primary CRC tumor and liver metastasis is different, hypoxia-inducible factor-1α (HIF-1α).
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