Toberer F, Haenssle H A, Heinzel-Gutenbrunner M, Enk A, Hartschuh W, Helmbold P, Kutzner H
Department of Dermatology, Venerology and Allergology, University Medical Center, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
MH-Statistical Consulting, Marburg, Germany.
J Eur Acad Dermatol Venereol. 2021 Jan;35(1):88-94. doi: 10.1111/jdv.16600. Epub 2020 Jun 15.
Metabolic reprogramming and altered gene expression mediated by hypoxia-inducible factors play crucial roles during tumour growth and progression. Nevertheless, studies analysing the expression of hypoxia-inducible factor-1α and its downstream targets in Merkel cell carcinoma (MCC) are lacking but are warranted to shed more light on MCC pathogenesis and to potentially provide new therapeutic options.
To analyse the immunohistochemical expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor-A (referred to as VEGF throughout the manuscript), VEGF receptor-2 (VEGFR-2), VEGF receptor-3 (VEGFR-3), glucose transporter-1 (Glut-1), monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CAIX) in primary cutaneous MCC.
The 16 paraffin-embedded primary cutaneous MCCs (Merkel cell polyomavirus (McPyV) positive/negative: 11/5) were analysed by immunohistochemistry, namely HIF-1α, VEGF, VEGFR-2 (KDR), VEGFR-3 (FLT4), Glut-1, MCT4 and CAIX. An established quantification score (QS) was applied to quantitate the protein expression by considering the percentage of positive tumour cells (0: 0%; 1: up to 1%; 2: 2-10%; 3: 11-50%; 4: >50%) in relation to the staining intensity (0: negative; 1: low; 2: medium; 3: strong).
HIF-1α was expressed in all MCCs and predominantly found at the invading edges of tumour margins. The HIF-1α downstream factors Glut-1, MCT4 and CAIX were expressed in 13 of 16 MCC (81%), 14 of 16 MCC (88%) and 16 of 16 MCC (100%), respectively. Interestingly, VEGF and VEGFR-2 were not expressed in tumour cells, whereas VEGFR-3 was expressed in all MCCs. HIF-1α was expressed significantly stronger in McPyV tumours (QS: 10.36 ± 2.41) than in McPyV tumours (QS: 5.40 ± 1.34; P = 0.002). Similarly, VEGFR-3 was also expressed significantly stronger in McPyV tumours (QS: 10.00 ± 2.52) than in McPyV tumours (QS: 5.40 ± 3.43, P = 0.019).
Our data provide first evidence for a role of HIF-1α in induced metabolic reprogramming contributing to MCC pathogenesis. The metabolic signatures of McPyV and McPyV tumours seem to show relevant differences.
缺氧诱导因子介导的代谢重编程和基因表达改变在肿瘤生长和进展过程中发挥着关键作用。然而，关于默克尔细胞癌（MCC）中缺氧诱导因子-1α及其下游靶点表达的分析研究尚缺，但有必要进行此类研究以更深入了解MCC的发病机制，并有可能提供新的治疗选择。
分析原发性皮肤MCC中缺氧诱导因子-1α（HIF-1α）、血管内皮生长因子-A（在本文中简称为VEGF）、VEGF受体-2（VEGFR-2）、VEGF受体-3（VEGFR-3）、葡萄糖转运蛋白-1（Glut-1）、单羧酸转运蛋白4（MCT4）和碳酸酐酶IX（CAIX）的免疫组化表达情况。
采用免疫组化方法对16例石蜡包埋的原发性皮肤MCC（默克尔细胞多瘤病毒（McPyV）阳性/阴性：11/5）进行分析，检测指标包括HIF-1α、VEGF、VEGFR-2（KDR）、VEGFR-3（FLT4）、Glut-1、MCT4和CAIX。应用既定的量化评分（QS）来定量蛋白质表达，该评分考虑了阳性肿瘤细胞的百分比（0：0%；1：高达1%；2：2%-10%；3：11%-50%；4：>50%）以及染色强度（0：阴性；1：低；2：中等；3：强）。
所有MCC中均有HIF-1α表达，且主要位于肿瘤边缘的浸润边缘。HIF-1α下游因子Glut-1、MCT4和CAIX分别在16例MCC中的13例（81%）、14例（88%）和16例（100%）中表达。有趣的是，肿瘤细胞中未检测到VEGF和VEGFR-2的表达，而所有MCC中均有VEGFR-3表达。HIF-1α在McPyV阳性肿瘤中的表达（QS：10.36±2.41）明显强于McPyV阴性肿瘤（QS：5.40±1.34；P=0.002）。同样，VEGFR-3在McPyV阳性肿瘤中的表达（QS：10.00±2.52）也明显强于McPyV阴性肿瘤（QS：5.40±3.）。
我们的数据首次证明了HIF-1α在诱导代谢重编程促进MCC发病机制中发挥作用。McPyV阳性和McPyV阴性肿瘤的代谢特征似乎存在显著差异。
