Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Jiefang Road No. 238, Wuhan, 430060, Hubei Province, China.
Department of General Surgery, Taihe Hospital, Hubei University of Medicine, Renmin South Road No. 32, Shiyan, 442000, Hubei Province, China.
Sci Rep. 2024 Apr 2;14(1):7733. doi: 10.1038/s41598-024-58424-w.
B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.
B-Myb 因其支持 DNA 修复的关键致癌功能而受到广泛关注。然而，其在结直肠癌中对化疗和免疫治疗的调节作用鲜有报道。硼替佐米（BTZ）是一种具有化疗和免疫治疗作用的新型化合物，但在高 B-Myb 表达的结直肠癌中无效。本研究旨在探讨结直肠癌中 B-Myb 缺失是否能增强 BTZ 对结直肠癌的免疫疗效，并阐明其潜在机制。在结直肠癌细胞中稳定诱导 B-Myb 敲低，与对照组相比，体外和体内均增加了癌细胞的凋亡。我们发现 BTZ 在 B-Myb 缺陷型结直肠癌细胞和荷瘤小鼠中表现出更有利的疗效。BTZ 处理导致富含 p53 信号通路的基因表达差异，促进了更强有力的下游 DNA 损伤，并使 B-Myb 缺陷型结直肠癌细胞的细胞周期停滞。相比之下，B-Myb 缺陷型结直肠癌细胞中 B-Myb 的恢复减弱了 BTZ 相关的 DNA 损伤、细胞周期停滞和抗癌疗效。此外，BTZ 促进了与 DNA 损伤相关的免疫原性增强，如 B-Myb 缺陷型细胞中 HMGB1 和 HSP90 的表达增强，从而驱动巨噬细胞向 M1 极化。总之，结直肠癌中 B-Myb 的缺失促进了癌细胞的免疫原性死亡，从而通过放大 DNA 损伤进一步增强 BTZ 的免疫疗效。本研究为结直肠癌免疫治疗提供了一个有效的 BTZ 分子靶点。
