Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Abstract

of HIF-1α and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm 2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value < 41.5/0.72 mm 2 . CONCLUSION:Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice. INTRODUCTIONAngiogenesis plays an important role in tumor growth and metastasis [1,2] . The formation of tumor microvessels is stimulated by angiogenic factors, especially vascular endothelial growth factor (VEGF) [3][4][5] . Hypoxia is related to tumor cell growth, differentiation, invasion and metastasis activity. In recent years, studies showed that hypoxia inducible factor-1 (HIF-1) played an important role in oxygen balance and tumor angiogenesis [6] . HIF-1 consists of α and β subunits, and HIF-1α is a key subunit of HIF activity regulated by hypoxia [1] . HIF-1 mRNA and protein overexpression was found in a variety of tumors, including breast cancer, prostate cancer, kidney cancer, rectal adenocarcinoma, etc [2,4,[7][8][9] . However, research on HIF-1α in gastric cancer was rarely reported. In the present study, BASIC RESEARCHUpregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma Abstract AIM:To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS:In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS:The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF-1α was positively correlated with VEGF protein. There were positive correlations between MVD and expression

Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer

“…To evaluate the statistically significant difference in the ratio of cancerous EPAS1 mRNA level to histopathologically unchanged tissue EPAS1 mRNA level between the three DNA methylation ranges (0%-1% methylation, 1%-10% methylation, and 10%-100% methylation), the nonparametric Kruskal-Wallis test was used. HIF1A mRNA levels were increased in cancerous compared with noncancerous tissue (8,11,12,33,34). However, other studies reported a constant HIF1A mRNA level in tumor cells and suggested mainly posttranslational regulation of HIF1A expression (35)(36)(37), which is consistent with our observations.…”

“…Many articles describe aberrant HIF1a or EPAS1 protein levels and their association with colorectal cancer prognosis (3)(4)(5)(6)(7)(8)(9)(10). However, there are only few articles about the same issues on the HIF1A and EPAS1 mRNA level (8,11,12). Moreover, relatively little is known about transcriptional regulation of HIF1A and EPAS1.…”

Prognostic significance of vascular endothelial growth factor expression in gastric carcinoma: a meta-analysis

“…The prognostic potential of VEGF immunohistochemical expression has been reported by many literatures (Cheng et al 2010;Wei et al 2009;Li et al 2008;Wang et al 2008;Liu et al 2007;Chen et al 2007;Han et al 2007;Ma et al 2007;Gao et al 2007;Lou et al 2005;Du et al 2003;Song et al 2002;Jiao et al 2005;Tang et al 2008;Yu et al 2003;Shi et al 2003;Feng et al 2002;Kolev et al 2007;Mizokami et al 2006;Urano et al 2006;Aoyagi et al 2005;Koga et al 2004;Kaneko et al 2003;Takahashi et al 2003;Kawabe et al 2002;Kimura et al 2001;Ichikura et al 2001;Kabashima et al 2001;Maehara et al 2000;Saito et al 1999;Tomoda et al 1999;Tanigawa et al 1997;Baba et al 1998;Maeda et al 1998;Lee et al 2009Lee et al , 2010Oh et al 2008;Choi et al 2006;Park et al 2005;Joo et al 2002Joo et al , 2003. And, the most widely studied prognostic factors on VEGF refer to variables including tumor size, location, his...…”

Angiogenesis inhibitors in gastric and gastroesophageal junction cancer

“…Particularly, under hypoxic conditions, HIF-1a serves as a transcription factor that targets several genes, including VEGF, and promotes an adaptive angiogenic response to hypoxia [30]. In clinical settings, it has been shown that HIF-1a is associated with tumor prognosis [31][32][33][34][35].…”