Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Nanakuma 7-45-1, Jonan-ku, Fukuoka, Japan.
Sci Rep. 2022 Aug 1;12(1):13208. doi: 10.1038/s41598-022-15926-9.
Cancer cells often metastasize to the lymph nodes (LNs) before disseminating throughout the body. Clinically, LN metastasis correlates with poor prognosis and influences treatment options. Many studies have shown that cancer cells communicate with immune and stromal cells to prepare a suitable niche for metastasis. In this study, mice were injected with B16-F10 murine melanoma cells to generate a tongue submandibular lymph node (SLN) metastasis model in which genes of interest could be investigated. Microarray analyses were performed on SLNs, identifying 162 upregulated genes, some of which are known metastasis genes. Among these upregulated genes, Kcne4, Slc7a11, Fscn1, and Gadd45b were not associated with metastasis, and increased expression of Kcne4 and Slc7a11 was confirmed by real-time PCR and immunohistochemistry. The roles of KCNE4 in chemokine production and cell adhesion were examined using primary lymphatic endothelial cells, and demonstrated that Ccl17 and Ccl19, which are involved in melanoma metastasis, were upregulated by KCNE4, as well as Mmp3 matrix metalloproteinase. Expression of KCNE4 was detected in human LNs with metastatic melanoma. In conclusion, we found that LN metastatic melanoma induces KCNE4 expression in the endothelium of LNs.
癌细胞在扩散到全身之前，通常会转移到淋巴结（LNs）。临床上，淋巴结转移与预后不良相关，并影响治疗选择。许多研究表明，癌细胞与免疫和基质细胞相互作用，为转移准备合适的生态位。在这项研究中，我们向小鼠注射 B16-F10 黑色素瘤细胞，生成一个舌下颌下淋巴结（SLN）转移模型，可在该模型中研究感兴趣的基因。对 SLNs 进行了微阵列分析，确定了 162 个上调基因，其中一些是已知的转移基因。在这些上调基因中，Kcne4、Slc7a11、Fscn1 和 Gadd45b 与转移无关，并且通过实时 PCR 和免疫组织化学证实了 Kcne4 和 Slc7a11 的表达增加。使用原代淋巴管内皮细胞研究了 KCNE4 在趋化因子产生和细胞黏附中的作用，结果表明，参与黑色素瘤转移的 Ccl17 和 Ccl19 以及 Mmp3 基质金属蛋白酶被 KCNE4 上调。在有转移性黑色素瘤的人类淋巴结中检测到 KCNE4 的表达。总之，我们发现淋巴结转移性黑色素瘤诱导淋巴结内皮细胞中 KCNE4 的表达。
