Abstract
Hypoxia inducible factor-1α (HIF-1α), induces cytokines such as CXCL8 and tumor dissemination, chemo- and radio-resistance. We analyzed correlation between HIF-1α and CXCL8 levels, tumor characteristics and overall survival in 102 hepatocellular carcinoma (HCC) patients. Levels of HIF-1α and CXCL8 were increased in HCC tissues and cell lines. Patients with high levels of HIF-1α and CXCL8 had worse outcome and poorer prognosis than those with lower levels. Co-overexpression of HIF-1α and CXCL8 was an independent negative prognostic factor for overall and disease-free survival. HIF-1α silencing and CXCL8 siRNA decreased migration under hypoxic conditions in vitro. Hypoxia-induced activation of AKT/mTOR/STAT3 pathways was reversed by depletion of CXCL8. We conclude that HIF-1α and CXCL8 induce HCC progression and metastasis, associated with activation of AKT/mTOR/STAT3. Co-expression of HIF-1α and CXCL8 is a prognostic marker and a potential therapeutic target in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer mortality worldwide [1,2,3,4]
Hypoxia inducible factor-1α (HIF-1α) and CXCL8 were detected in paraffinembedded serial sections from 102 HCC patients, which underwent hepatectomy
Expression of HIF-1α and CXCL8 was higher in HCC tissues compared to adjacent www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget non-tumor liver tissues (Figure 1A)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer mortality worldwide [1,2,3,4]. Interleukin-8 (IL-8), known as CXCL8, is a chemokine with tumorigenic and angiogenic properties [9]. It is secreted by inflammatory and tumor cells. Hypoxia inducible factor-1α (HIF1α) stimulates cytokines expression, increases tumor dissemination, cell proliferation, angiogenesis and survival [13,14,15,16]. We investigated the relations between CXCL8 and HIF-1α and evaluated prognostic and therapeutic values of CXCL8 and HIF-1α in a large group of HCC patients based on a decade of follow-up
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