Relationship Between Preoperative Plasma Hypoxia - Inducible Factor - 1a (HIF - 1a) Levels And HIF - 1a, VEGF Protein Levels In Patients With Non - Small Cell Lung Cancer And Its Clinical Significance

Background and objective: Hypoxia has long been recognized as a common featureof solid tumors. Hypoxia-inducible factor1a (HIF-1a) is a master regulator of thetranscriptional response of tumor cells to oxygen deprivation. HIF-1a may play animportant role in the process of non-small cell lung cancer (NSCLC). Therefore, theaim of this study was to evaluate the relationship between HIF-1a plasma level andexpression in tissue, and the relationship between them and VEGF expression intissue. To investigate the role of HIF-1a and VEGF in the clinical pathology to furtherexplore whether the markers can be used in patients with NSCLC.Methods: HIF-1a and VEGF expressions were detected using immunohistochemistry(IHC) in the paraffin-embedded sections made from the surgical primary tumors of215patients with NSCLC. HIF-1a levels were measured in the plasma collected in101patients among the whole patients using enzyme linked immunosorbent assay(ELISA) and60healthy volunteers were measured synchronously. Relationshipbetween the markers and the clinical pathological significance were analyzed.Results:1) HIF-1a was expressed both in nucleus and cytoplasm. According to the HIF-1a staining score of tumor nucleus,68.4%(147/215)were staining more than0%inNSCLC patients; According to the HIF-1a staining score of tumor cytoplasm,53.0%(114/215)were staining positive. According to the HIF-1a staining score of bothtumor cytoplasm and nucleus,73.0%(157/215)were staining positive.2) Among patients with squamous carcinoma, HIF-1a was staining with a higherproportion which was41.0%(48/117)compared with20.3%(16/79)in patients withadenocarcinomas (P=0.002). HIF-1a presented a lower staining proportion in patientswhose tumor was smaller than4cm compared with those tumor was larger than4cm(P=0.009). Patients with T1staging expressed a lower HIF-1a than patients withT2-4staging(P=0.035);3) The positive staining of VEGF was73.5%(158/215). VEGF was82.3%(65/79)positive in patients with adenocarcinoma that was higher than the positive expressionof69.4%(80/117, P=0.030)in patients with squamous carcinoma. Female patients hada higher expression of VEGF than male patients(P=0.009); Patients with staging IIIhad a higher expression of VEGF than those patients staging I-II(P=0.047).4) Plasms HIF-1a levels of NSCLC patients were significantly higher than thehealthy(P=0.026); Plasms HIF-1a levels associated with the expressions of HIF-1a intumor tissue,but not associated with VEGF expression(P>0.05). According to theHIF-1a staining score of both tumor cytoplasm and nucleus, a positive relation wasfound between HIF-1a and VEGF expression in tissuey(P=0.026). No correlation wasfound between nuclear or cytoplasm HIF-1a and VEGF expression(P>0.05).Conclusions: HIF-1a was expressed higher in squamous carcinoma, and correlatedwith tumor size and T staging; VEGF was expressed higher in adenocarcinoma, andcorrelated with gender and TNM staging; There was an association between plasma HIF-1a and tissue HIF-1a. Plasma HIF-1a level could reflect the level of HIF-1a intumor tissue in some extent. HIF-1a staining score of both tumor cytoplasm andnucleus correlates with VEGF in tissue. Background and objective: Non-small cell lung cancer(NSCLC)is the most commonhistology type of lung cancer.80%of lung cancer is NSCLC. Surgery is the mostimportant treatment of Ia-IIIa staging patients. Recurrence and metastasis are still themajor reasons related to the mortality of the operable NSCLC. Established effectivebiomarkers to predict the prognosis and the effects of treatment is necessary whichcould help to understand the clinical status more accurately. Many reports haveresulted with some biomarkers, vascular endothelial growth factor(VEGF)andhypoxia-inducible factor(HIF-1a)among them were suggested to have the prognosticsignificance.Methods: Follow-up the patients who had been detected HIF-1a and VEGFexpression in tumor tissues. According to their survival materials, analyze theprognostic factors. The whole numbers of the patients were211with100patientsamong them had been measured preoperative plasma HIF-1a level.Results:1) The1styear,3rdyear and5thyear survival rate were87.7%(185/211),64.9%(137/211)and55.4%(102/184)respectively. Staging I, II and III patients with a5thyearsurvival rate of75.3%,54.5%and28.8%;2) Tumor size, local N status, pTNM staging and nuclear HIF-1a expressionassociated with the patients prognosis(P<0.05); 3) Plasma HIF-1a level associated with the survival rate of patients with squamouscarcinoma. As cut by297.70pg/ml, the low group had a longer survival time than thehigh group,74.1%and52.2%, respectively(P=0.048);4) Univariate analysis suggested tumor size, pTNM staging and nuclear HIF-1aexpression were the prognostic factors(P<0.05)and multivariate analysis came to aresult that pTNM staging and nuclear HIF-1a expression were the independentprognostic factors(P<0.05); The same results were attained in subgroup of squamouscarcinoma patients(P<0.05). But nuclear HIF-1a expression was not the prognosticfactor in patients with adenocarcinoma(P=0.270).5) No associations were found between VEGF expression and the prognosisof patients with NSCLC(P=0.413).6) Nuclear HIF-1a level may be the most suitable status to reflect the activatedHIF-1.Conclusions: Nuclear HIF-1a level was associated with the5thyear survival rate ofpatients with NSCLC. pTNM staging and nuclear HIF-1a level were the independentprognostic factor as the same result in patients with squamous carcinoma. PlasmaHIF-1a level associated with the survival rate of patients with squamous carcinoma.When the tissue is impossible to get plasma HIF-1a level might be used to reflect theactivated HIF-1a. HIF-1a has the better value as a prognostic factor than VEGF topatients with NSCLC.