Locoregional control is a significant prognostic factor for hepatocellular carcinoma (HCC). Historically, the use of radiotherapy (RT) for HCC was limited owing to the low radiotolerance of the liver and the need for high RT doses for disease control. We aimed to examine if 1α,25-dihydroxyvitamin D3 (calcitriol) has a role in the tumor inhibition and the radiation response of HCC in vitro and in vivo, and explore the underlying mechanisms. The human and murine liver cancer cell lines were selected for cellular and animal experiments to investigate the changes in tumor characteristics and the radiation response after calcitriol supplementation. The effects induced by calcitriol supplementation on interleukin-6 (IL-6) signaling and the tumor immune microenvironment following RT were also examined. Our data revealed that calcitriol supplementation attenuated tumor aggressive behavior, decrease IL-6 expression, and augmented radiation-induced tumor inhibition. The biological changes following calcitriol treatment included suppressed epithelial-mesenchymal transition, attenuated cancer stem cell-like properties and increased radiation-induced reactive oxygen species and cell death in vitro. Regarding immune microenvironment, calcitriol attenuated the recruitment of myeloid-derived suppressor cell (MDSC) recruitment and increased the infiltration of cytotoxic T cells in tumor following RT. Furthermore, When the primary liver tumor was irradiated with larger dose per fraction, calcitriol induced a smaller size of synchronous unirradiated tumor in mice, which linked with attenuated IL-6 signaling and MDSC recruitment. In conclusion, calcitriol treatment reduced tumor aggressiveness and enhanced the radiation response. The inhibited IL-6 signaling and subsequently enhanced antitumor immunity might be responsible to augment radiation-induced tumoricidal effect induced by calcitriol. Based on our results, we suggest that calcitriol could exert the antitumor and radiosensitization effects for HCC, especially for multifocal tumors.

中文翻译：

---

维生素 D3 在肝细胞癌肿瘤侵袭性和放射反应中的作用

局部区域控制是肝细胞癌（HCC）的重要预后因素。从历史上看，由于肝脏的放射耐受性低以及需要高剂量的放疗来控制疾病，因此对 HCC 的放疗 (RT) 的使用受到限制。我们旨在研究 1α,25-二羟基维生素 D3（骨化三醇）是否在体外和体内对 HCC 的肿瘤抑制和放射反应起作用，并探索其潜在机制。选择人和鼠肝癌细胞系进行细胞和动物实验，以研究补充骨化三醇后肿瘤特征和辐射反应的变化。还检查了补充骨化三醇对白细胞介素 6 (IL-6) 信号传导和 RT 后肿瘤免疫微环境的影响。我们的数据显示，补充骨化三醇可减弱肿瘤侵袭行为、降低 IL-6 表达并增强辐射诱导的肿瘤抑制作用。骨化三醇治疗后的生物学变化包括抑制上皮-间质转化、减弱癌症干细胞样特性和增加辐射诱导的活性氧和体外细胞死亡。关于免疫微环境，骨化三醇减弱了骨髓源性抑制细胞 (MDSC) 的募集，并增加了放疗后肿瘤中细胞毒性 T 细胞的浸润。此外，当原发性肝肿瘤每次照射较大剂量时，骨化三醇会在小鼠中诱导较小尺寸的同步未照射肿瘤，这与减弱的 IL-6 信号传导和 MDSC 募集有关。综上所述，骨化三醇治疗降低了肿瘤侵袭性并增强了放射反应。抑制的 IL-6 信号传导和随后增强的抗肿瘤免疫可能是增强骨化三醇诱导的辐射诱导的肿瘤杀伤作用的原因。基于我们的研究结果，我们认为骨化三醇可以对 HCC，尤其是多灶性肿瘤发挥抗肿瘤和放射增敏作用。