Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
Clinic of Urology and Pediatric Urology, FA University Hospital Erlangen-Nuremberg, 91054 Erlangen, Germany.
Int J Mol Sci. 2018 Dec 3;19(12):3842. doi: 10.3390/ijms19123842.
In various tumors, the hypoxia inducible factor-1α () and the epidermal growth factor-receptor () 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; = 0.001 and RR = 1.9; = 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, = 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, = 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 ( < 0.001) or EGFR protein ( = 0.001) was found, additionally, EGFR mRNA correlated with EGFR protein level ( < 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.
在各种肿瘤中，缺氧诱导因子-1α（HIF-1α）和表皮生长因子受体（EGFR）对生存有影响。然而，这两个标志物对软组织肉瘤（STS）的预后影响尚未得到很好的研究。我们检测了 114 例成人软组织肉瘤患者的冷冻肿瘤样本和 19 例冷冻正常组织样本。使用多重 qPCR 技术定量检测 HIF-1α、EGFR 和参考基因次黄嘌呤磷酸核糖基转移酶（HPRT）的 mRNA 水平。此外，使用 ELISA 技术从 74 个相应的蛋白质样本中确定 EGFR 或 HIF-1α 蛋白的水平。我们的分析表明，HIF-1α 或 EGFR mRNA 水平较低（分别为相对风险（RR）= 2.8； = 0.001 和 RR = 1.9； = 0.04；多变量 Cox 回归分析）与 STS 患者预后不良显著相关。当肿瘤中两种 mRNA 水平均较低时，多变量 Cox 回归分析中的这两种 mRNA 的组合导致患者早期肿瘤特异性死亡的风险增加（RR = 3.1， = 0.003）。EGFR 蛋白水平与所研究患者队列的生存无关联，而 HIF-1α 蛋白水平较高仅与 STS 患者预后的显著趋势相关（多变量 Cox 回归分析）（RR = 1.9， = 0.09）。然而，与 HIF-1α 蛋白水平和 EGFR 蛋白无这种组合的患者相比，肿瘤中 HIF-1α 蛋白水平较低且 EGFR 含量较高的患者的生存率提高了三倍。在双变量双侧 Spearman 秩相关分析中，发现 HIF-1α mRNA 的表达与 EGFR mRNA（ < 0.001）或 EGFR 蛋白（ = 0.001）的表达之间存在显著相关性，此外，EGFR mRNA 与 EGFR 蛋白水平相关（ < 0.001）。我们的结果表明，低水平的 HIF-1α mRNA 或 EGFR mRNA 是 STS 患者的阴性独立预后标志物，尤其是在联合两种参数后。蛋白质水平对预后有不同的影响。此外，我们的分析表明 HIF-1α 和 EGFR 在 STS 中的表达之间可能存在关联。
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