Co-expression Of Hypoxia-inducible Factor-1α And Hepatocyte Growth Factor In Non-small-cell Lung Cancer And Their Association With Lymphangiogenesis

Primary lung cancer is one of the most common malignant tumors worldwide, with both morbidity and mortality showing an increasing trend. Non-small-cell lung cancer (NSCLC) accounts for more than two-thirds of primary lung cancer. Metastasis in NSCLC includes regional spread, lymphatic metastasis, hematogenous metastasis and airway metastasis. Lymphatic metastasis,which is the main mode in NSCLC and can occur when the diameter of the tumor is<2cm, is an important factor affecting clinical treatment and prognosis.Tumorogenesis of malignant tumors is associated with cell over proliferation, and tumor proliferation consumes lots of oxygen, so hypoxia is one of the common features in solid tumor microenvironment. Hypoxia-inducible factor-1(HIF-1) is a transcription factor that exists widely in mammals and human body cells. It has been confirmed by studies that HIF-1α, which was closely associated with tumor growth, invasion and metastasis, neovascularization, apoptosis and drug-resistance, could abundantly express in lots of human tumors.Hepatocyte growth factor (HGF), also known as scatter factor (SF), was originally described that can strongly stimulate regeneration of hepatocytes. It has been proved by previous studies that HGF plays an important role in fetal development, organ formation, and tumor invasion, metastasis and angiogenesis. It has been shown by recent study that HGF may be also a potent factor that contributes to tumor lymphangiogenesis. D2-40, which is a newly found novel monoclonal antibody that specifically reacts with marked lymphatic vessels, has been identified as specific markers for tumor lymphangiogenesis research. The correlation studies about HIF-la and HGF in NSCLC have not been reported so far.Objective:To investigate the co-expression of hypoxia-inducible factor-1α (HIF-1α) and hepatocyte growth factor (HGF) and their association with lymphangiogenesis in non-small-cell lung cancer (NSCLC).Methods:Applying the immunohistochemical technique, the lymphatic microvessel density (LMVD) was counted and the expression of HIF-1α and HGF in126patients with NSCLC and20peri-cancerous normal lung tisuue samples were determined Relationships of expression of HIF-1α and HGF with LMVD and clinicopathologic factors were analyzed. The SPSS18.0statistical software was used for statistical analysis, a P<0.05was considered statistically significant.Results:1. The expression of HIF-1α in NSCLC tissues HIF-1α was found high expressed in NSCLC tissues, Hif-1α was observed mainly expressed in the cellular nucleus. Of126patients with NSCLC, the positive expression rate of HIF-1α was85.7%, however, in20cases of peri-cancerous normal tissues, the positive expression rate of HIF-1α was20%, so expression of HIF-1α in peri-cancerous normal tissues was significantly lower than in NSCLC tissues, there was statistical significance(P<0.05); expression of HIF-1α was significantly associated with TNM stage and lymph node metastasis (P<0.05), while expression of HIF-1α had no significant correlation with age, sex, tumor size, histological type and differentiation grade (P>0.05).2. The expression of HGF in NSCLC tissues HGF was found high expressed in NSCLC tissues, HGF was observed mainly expressed in the membrane and cytoplasm of lung tumor cells. Of126patients with NSCLC, the positive expression rate of HGF was80.9%, compared with25%in20cases of peri-cancerous normal tissues, so expression of HGF in peri-cancerous normal tissues was significantly lower than in NSCLC tissues, there was statistical significance(P<0.05); expression of HGF was significantly associated with TNM stage and lymph node metastasis (P<0.05), while expression of HGF had no significant correlation with age, sex, tumor size, histological type and differentiation grade (P>0.05).3. Coexpression of HIF-1α and HGF in NSCLC tissues Of108NSCLC tissues with positive expression of HIF-1α, there were also102NSCLC tissues with positive expression of HGF, by the analysis of linear correlation, the expression of HIF-1α was strongly positive correlated to HGF expression in NSCLC tissues (R2=0.590P<0.05).4. The expression of LMVD was significantly higher in NSCLC tisuues than in peri-cancerous normal tissues(P<0.05). The expression of LMVD had no significant correlation to age, gender, histological type, tumor-size and differentiation grade(P>0.05). However, the expression of LMVD was significantly associated with TNM stage and lymph nodes metastasis (P<0.05).5. Association of expression of HIF-1α、HGF and LMVD In NSCLC tissues, the positive expression intensity of HIF-1α and HGF was significantly positive associated with LMVD (P<0.05)Conclusion:Coexpression of HIF-1α and HGF exists in NSCLC, significant correlation was found between expression of HIF-1α and HGF, moreover, expression of HIF-1α and HGF were both associated with LMVD and lymph node metastasis, this suggests that overexpression of HIF-1α and HGF can promote lymphangiogenesis, and study of those relevant inhibitors may make great good to patiences with lymphatic and distal metastasis in NSCLC.