Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, 50139 Florence, Italy.
Advanced Bioimaging Research Laboratory (ABiR), University of Florence, 50139 Florence, Italy.
Cells. 2021 Nov 11;10(11):3131. doi: 10.3390/cells10113131.
Macrophages (MΦs) and reactive oxygen species (ROS) are implicated in carcinogenesis. The oxidative stress sensor, transient receptor potential ankyrin 1 (TRPA1), activated by ROS, appears to contribute to lung and breast cancer progression. Although TRPA1 expression has been reported in melanoma cell lines, and oxidative stress has been associated with melanocytic transformation, their role in melanoma remains poorly known. Here, we localized MΦs, the final end-product of oxidative stress, 4-hydroxynonenal (4-HNE), and TRPA1 in tissue samples of human common dermal melanocytic nevi, dysplastic nevi, and thin (pT1) and thick (pT4) cutaneous melanomas. The number (amount) of intratumoral and peritumoral M2 MΦs and 4-HNE staining progressively increased with tumor severity, while TRPA1 expression was similar in all samples. Hydrogen peroxide (HO) evoked a TRPA1-dependent calcium response in two distinct melanoma cell lines (SK-MEL-28 and WM266-4). Furthermore, HO induced a TRPA1-dependent HO release that was prevented by the TRPA1 antagonist, A967079, or gene silencing (siRNA). ROS release from infiltrating M2 MΦs may target TRPA1-expressing melanoma cells to amplify the oxidative stress signal that affects tumor cell survival and proliferation.
巨噬细胞（MΦs）和活性氧（ROS）被认为与致癌作用有关。ROS 激活的氧化应激感受器瞬时受体电位锚蛋白 1（TRPA1）似乎有助于肺癌和乳腺癌的进展。尽管 TRPA1 表达已在黑色素瘤细胞系中报道，并且氧化应激与黑素细胞转化有关，但它们在黑色素瘤中的作用仍知之甚少。在这里，我们在人常见的皮肤黑色素细胞痣、发育不良痣以及薄（pT1）和厚（pT4）皮肤黑色素瘤的组织样本中定位了巨噬细胞（ROS 的最终产物）、4-羟基壬烯醛（4-HNE）和 TRPA1。肿瘤严重程度的增加与肿瘤内和肿瘤周围 M2 巨噬细胞数量（量）和 4-HNE 染色逐渐增加，而所有样本中 TRPA1 的表达相似。过氧化氢（HO）在两种不同的黑色素瘤细胞系（SK-MEL-28 和 WM266-4）中诱发了依赖于 TRPA1 的钙反应。此外，HO 诱导了依赖于 TRPA1 的 HO 释放，这种释放被 TRPA1 拮抗剂 A967079 或基因沉默（siRNA）所阻止。浸润性 M2 巨噬细胞释放的 ROS 可能靶向表达 TRPA1 的黑色素瘤细胞，以放大影响肿瘤细胞存活和增殖的氧化应激信号。
