Background: Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma that primarily affects the skin, rich in hyaluronic acid (HA). HA is a component of the extracellular matrix in the dermis and likely affects the development of CTCL, but the mechanism is poorly understood. Here we show that low-molecular-weight HA (LMWHA) possibly exacerbates CTCL, and bexarotene, already used in CTCL treatment, decreases HA production. Methods: We conducted immunohistochemistry, qRT-PCR, immunoblotting, and HA quantification using both mouse and human specimens to evaluate the impact of HA on CTCL. Additionally, we assessed the effect of bexarotene, which is already used for CTCL treatment, on HA metabolism. Results: HA expression was higher in patients’ serum and skin sections than in healthy controls. HA extracted from the skin of mice inoculated with tumors showed an increase in LMWHA. LMWHA increased lymphoma cell proliferation in vitro and accelerated tumor formation in mice in vivo. LMWHA also created a favorable environment for tumor cells by affecting fibroblasts, vascular endothelial cells, and tumor-associated macrophages. Thus, increased levels of HA, mainly LMWHA, exacerbate CTCL progression by affecting tumor cells and their microenvironment. Bexarotene treatment reduced the amount of total HA in murine tumor-inoculated skin, as well as the supernatant of cultured normal human dermal fibroblasts (NHDFs) and HuT78 cells. Detailed in vitro analyses showed that bexarotene treatment decreased HA synthase (HAS)1 and HAS2 expression in NHDFs and HAS1 and HAS3, and CEMIP expression in HuT78 cells. Chromatin immunoprecipitation assays revealed that bexarotene reduced retinoid X receptor-α binding to theHAS1andHAS2promoters in NHDFs. Conclusions: Bexarotene potentially exerts its anti-tumor effect by reducing HA levels through decreased expression of HAS. These findings provide new insights into the process of CTCL development and additional insights regarding bexarotene treatment.
背景：皮肤T细胞淋巴瘤（CTCL）是一种主要累及富含透明质酸（HA）皮肤的非霍奇金淋巴瘤。HA是真皮细胞外基质的组成部分，可能影响CTCL的发展，但其机制尚不清楚。本文研究表明，低分子量透明质酸（LMWHA）可能加剧CTCL，而已用于CTCL治疗的贝沙罗汀可减少HA的产生。 方法：我们采用小鼠和人类标本进行免疫组化、qRT-PCR、免疫印迹和HA定量分析，以评估HA对CTCL的影响。此外，我们还评估了已用于CTCL治疗的贝沙罗汀对HA代谢的影响。 结果：患者血清和皮肤切片中的HA表达高于健康对照组。从接种肿瘤的小鼠皮肤中提取的HA显示LMWHA增加。LMWHA在体外促进淋巴瘤细胞增殖，并在体内加速小鼠肿瘤形成。LMWHA还通过影响成纤维细胞、血管内皮细胞和肿瘤相关巨噬细胞，为肿瘤细胞创造有利环境。因此，HA（主要是LMWHA）水平升高通过影响肿瘤细胞及其微环境加剧CTCL进展。贝沙罗汀治疗降低了小鼠肿瘤接种皮肤、培养的正常人真皮成纤维细胞（NHDFs）和HuT78细胞上清液中的总HA量。详细的体外分析显示，贝沙罗汀处理降低了NHDFs中HA合成酶（HAS）1和HAS2的表达，以及HuT78细胞中HAS1、HAS3和CEMIP的表达。染色质免疫沉淀实验表明，贝沙罗汀减少了视黄醇X受体-α与NHDFs中HAS1和HAS2启动子的结合。 结论：贝沙罗汀可能通过降低HAS表达来减少HA水平，从而发挥其抗肿瘤作用。这些发现为CTCL发展过程提供了新的见解，并为贝沙罗汀治疗提供了更多依据。
肿瘤(癌症)患者之家