Expression of Hypoxia-Inducible Factor-1α Protein Predicts Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract

Abstract

Hypoxia-inducible factor-1 (HIF-1), identified as one of the transcription factors, has been found to play an essential role in oxygen homeostasis. HIF-1is a heterodimer composed of HIF-1a and HIF-1h. Increased levels of HIF-1a have been reported during the carcinogenesis and progress of several tumors.We investigated the prognostic importance of HIF-1a expression in transitional cell carcinoma of the upper urinary tract. In 127 cases of transitional cell carcinoma of the upper urinary tract, we examined its expression (using immunohistochemistry and in situ hybridization), and also its relation to the expression of p53 oncoprotein, as well as to proliferating cell nuclear antigen (PCNA) immunoreactivity, microvessel density, clinicopathologic parameters, and clinical outcome. A positive expression of HIF-1a protein was recognized in 55.1% of samples, the expression being apparent within the nucleus in tumor cells. HIF-1a protein expression correlated with grade, growth pattern, p53 oncoprotein expression, and PCNA index, but not with stage. Furthermore, a significant correlation was found between HIF-1a protein expression and both overall and disease-free survival rates in the univariate and multivariate analyses (in all tumors and in invasive tumors). A positive expression of HIF-1a mRNA was recognized in 69.6% of 125 samples which were available, the expression being apparent within the cytoplasm in tumor cells.The positive expression of HIF-1a mRNA by in situ hybridization correlated significantly with HIF-1a protein expression by immunohistochemistry. HIF-1a mRNA expression only correlated with pattern of growth (P = 0.0078). In conclusion, the detection of HIF-1a protein would seem to be of value in informing the prognosis of transitional cell carcinoma of the upper urinary tract.

Hypoxia-inducible factor-1α expression predicts the response to 5-fluorouracil-based adjuvant chemotherapy in advanced gastric cancer

“…We further reported a significant correlation between the HIF-1· expression and poor prognosis in patients with pancreatic cancer (32). Other studies have also reported a significant association between HIF-1· expression and prognosis in a variety of human cancers including stomach (17), esophagus (18), pancreas (19), lung (20), breast (21), upper urinary tract (22), uterine cervix (23) and ovarian cancer (24). However, few studies have so far addressed the clinical implications of the HIF-1· expression in regard to either chemosensitivity or chemoresistance in cancer patients.…”

“…More than 60 genes which are involved in glucose transport, angiogenesis, erythropoiesis, vasomotor regulation and survival of cancer cells harbor HREs on the regulatory regions and are activated by HIF-1· (15,16). Numerous studies have demonstrated a significant association between the overexpression of HIF-1· protein and tumor aggressiveness or a poor prognosis in several tumors, including gastric cancer (17)(18)(19)(20)(21)(22)(23)(24). Furthermore, growing evidence suggests that hypoxia in tumors selects for cells with decreased potential for apoptosis through the overexpression of anti-apoptotic proteins and decreased killing effects through the up-regulation of drug transporter proteins, thus indicating the involvement of HIF-1· in resistance to standard radiation therapy and chemotherapy under hypoxia (25)(26)(27)(28)(29).…”

Survival of patients with upper urinary tract urothelial carcinoma after nephroureterectomy and risk factors for bladder cancer

“…Proučavani su različiti proteini uključeni u fenomen ćelijske athezije, proliferacije, apoptoze i regulacije ćelijskog ciklusa [66][67][68][69]. Rađena su imunohistohemijska ispitivanja vezana za ćelijsku atheziju.…”

“…Ekspresija hipoksija-inducibilnog faktora 1α koji učestvuje u angiogenezi, pokazuje povezanost sa pojavom recidiva tumora i sa ukupnim mortalitetom od tumora gornjeg urotelijuma [68]. Takođe je dokazana povezanost ekspresije antigena KI-67, markera ćelijske proliferacije, sa patohistološkim stadijumom i gradusom tumora gornjeg urotelijuma [69].…”

“…Molekularni markeri, od značaja za dijagnozu i prognozu tumora gornjeg urotelijuma, ispitivani su od strane nekoliko istraživača [66][67][68][69]. Nestabilnost mikrosatelitskih regiona 1-7.…”