Abstract
In various tumors, the hypoxia inducible factor-1α (HIF-1α) and the epidermal growth factor-receptor (EGFR) have an impact on survival. Nevertheless, the prognostic impact of both markers for soft tissue sarcoma (STS) is not well studied. We examined 114 frozen tumor samples from adult soft tissue sarcoma patients and 19 frozen normal tissue samples. The mRNA levels of HIF-1α, EGFR, and the reference gene hypoxanthine phosphoribosyltransferase (HPRT) were quantified using a multiplex qPCR technique. In addition, levels of EGFR or HIF-1α protein were determined from 74 corresponding protein samples using ELISA techniques. Our analysis showed that a low level of HIF-1α or EGFR mRNA (respectively, relative risk (RR) = 2.8; p = 0.001 and RR = 1.9; p = 0.04; multivariate Cox´s regression analysis) is significantly associated with a poor prognosis in STS patients. The combination of both mRNAs in a multivariate Cox’s regression analysis resulted in an increased risk of early tumor-specific death of patients (RR = 3.1, p = 0.003) when both mRNA levels in the tumors were low. The EGFR protein level had no association with the survival of the patient’s cohort studied, and a higher level of HIF-1α protein associated only with a trend to significance (multivariate Cox’s regression analysis) to a poor prognosis in STS patients (RR = 1.9, p = 0.09). However, patients with low levels of HIF-1α protein and a high content of EGFR protein in the tumor had a three-fold better survival compared to patients without such constellation regarding the protein level of HIF-1α and EGFR. In a bivariate two-sided Spearman’s rank correlation, a significant correlation between the expression of HIF-1α mRNA and expression of EGFR mRNA (p < 0.001) or EGFR protein (p = 0.001) was found, additionally, EGFR mRNA correlated with EGFR protein level (p < 0.001). Our results show that low levels of HIF-1α mRNA or EGFR mRNA are negative independent prognostic markers for STS patients, especially after combination of both parameters. The protein levels showed a different effect on the prognosis. In addition, our analysis suggests a possible association between HIF-1α and EGFR expression in STS.
Highlights
Soft tissue sarcomas (STS) are a heterogeneous group of relatively aggressive tumors of mesenchymal origin [1,2]
We separated the cohort of soft tissue sarcoma (STS) patients into two groups according to the median expression of hypoxia inducible factor-1α (HIF-1α) and epidermal growth factor-receptor (EGFR) mRNA
High-level expression of HIF-1α and EGFR was defined as a relative value above 4.7 copies HIF1α mRNA and 1.5 copies EGFR
Summary
Soft tissue sarcomas (STS) are a heterogeneous group of relatively aggressive tumors of mesenchymal origin [1,2]. New prognostic markers are required that have the potential to assess the effectiveness of an individual therapeutic strategy. A potential prognostic marker for STS could be hypoxia inducible factor-1α (HIF-1α), which is the inducible subunit of the transcription factor HIF-1. It is commonly thought to be the most important marker of mammalian cell transcriptional response to oxygen deprivation. High expression of HIF-1α protein in various cancers including cervical, head and neck and oropharyngeal carcinoma was correlated with an unfavorable prognosis [4,5,6]. In other studies, high expression of HIF-1α protein correlated with good prognosis, such as lung cancer, squamous cell carcinoma, or renal cell carcinoma [7,8,9]
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