Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
J Transl Med. 2024 Jan 30;22(1):117. doi: 10.1186/s12967-024-04931-3.
Radioresistance is a primary factor contributing to the failure of rectal cancer treatment. Immune suppression plays a significant role in the development of radioresistance. We have investigated the potential role of phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) in regulating immune suppression associated with radioresistance.
To elucidate the mechanisms by which PITPNC1 influences radioresistance, we established HT29, SW480, and MC38 radioresistant cell lines. The relationship between radioresistance and changes in the proportion of immune cells was verified through subcutaneous tumor models and flow cytometry. Changes in the expression levels of PITPNC1, FASN, and CD155 were determined using immunohistochemistry and western blotting techniques. The interplay between these proteins was investigated using immunofluorescence co-localization and immunoprecipitation assays. Additionally, siRNA and lentivirus-mediated gene knockdown or overexpression, as well as co-culture of tumor cells with PBMCs or CD8 T cells and establishment of stable transgenic cell lines in vivo, were employed to validate the impact of the PITPNC1/FASN/CD155 pathway on CD8 T cell immune function.
Under irradiation, the apoptosis rate and expression of apoptosis-related proteins in radioresistant colorectal cancer cell lines were significantly decreased, while the cell proliferation rate increased. In radioresistant tumor-bearing mice, the proportion of CD8 T cells and IFN-γ production within immune cells decreased. Immunohistochemical analysis of human and animal tissue specimens resistant to radiotherapy showed a significant increase in the expression levels of PITPNC1, FASN, and CD155. Gene knockdown and rescue experiments demonstrated that PITPNC1 can regulate the expression of CD155 on the surface of tumor cells through FASN. In addition, co-culture experiments and in vivo tumor-bearing experiments have shown that silencing PITPNC1 can inhibit FASN/CD155, enhance CD8 T cell immune function, promote colorectal cancer cell death, and ultimately reduce radioresistance in tumor-bearing models.
PITPNC1 regulates the expression of CD155 through FASN, inhibits CD8 T cell immune function, and promotes radioresistance in rectal cancer.
放射抵抗是直肠癌治疗失败的主要因素。免疫抑制在放射抵抗的发展中起着重要作用。我们研究了磷酸肌醇转移蛋白细胞质 1（PITPNC1）在调节与放射抵抗相关的免疫抑制中的潜在作用。
为了阐明 PITPNC1 影响放射抵抗的机制，我们建立了 HT29、SW480 和 MC38 放射抵抗细胞系。通过皮下肿瘤模型和流式细胞术验证放射抵抗与免疫细胞比例变化之间的关系。使用免疫组织化学和 Western blot 技术确定 PITPNC1、FASN 和 CD155 的表达水平变化。使用免疫荧光共定位和免疫沉淀实验研究这些蛋白质之间的相互作用。此外，还使用 siRNA 和慢病毒介导的基因敲低或过表达以及肿瘤细胞与 PBMC 或 CD8 T 细胞共培养，并在体内建立稳定的转基因细胞系，验证了 PITPNC1/FASN/CD155 途径对 CD8 T 细胞免疫功能的影响。
在照射下，放射抵抗结直肠癌细胞系的细胞凋亡率和凋亡相关蛋白的表达明显降低，而细胞增殖率增加。在放射抵抗荷瘤小鼠中，免疫细胞中 CD8 T 细胞和 IFN-γ产生的比例下降。对放射抵抗的人类和动物组织标本的免疫组织化学分析显示，PITPNC1、FASN 和 CD155 的表达水平显著增加。基因敲低和挽救实验表明，PITPNC1 可以通过 FASN 调节肿瘤细胞表面 CD155 的表达。此外，共培养实验和体内荷瘤实验表明，沉默 PITPNC1 可以抑制 FASN/CD155，增强 CD8 T 细胞免疫功能，促进结直肠癌细胞死亡，最终降低荷瘤模型中的放射抵抗。
PITPNC1 通过 FASN 调节 CD155 的表达，抑制 CD8 T 细胞免疫功能，促进直肠癌的放射抵抗。
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