摘要
      5-氟尿嘧啶（5-FU）耐药性的出现是大肠癌（CRC）患者有效临床结局的障碍。自噬被发现与保护肿瘤细胞免受5-FU的侵害有关。然而，自噬相关基因在CRC 5-FU耐药性中的具体作用尚不清楚。在本研究中，在CRC中34个差异表达的ARGs中，HSPB8被鉴定为5-FU耐药的中枢ARGs，与正常样本相比，其在CRC样本中下调，但在CRC淋巴浸润相对较高、晚期和预后较差的CRC样本中上调。机制分析表明，由于CAFs的募集，HSPB8在CRC细胞中的表达增强，因此HSPB8可以与其共同伴侣BAG3一起在自噬驱动的5-FU耐药性中发挥作用。此外，HSPB8表达水平的增加与Treg细胞、巨噬细胞、单核细胞和树突状细胞等免疫细胞的浸润显著相关。我们的研究结果表明，CAFs通过促进肿瘤自噬来驱动HSPB8诱导的CRC 5-FU耐药性，将为寻找潜在的CRC治疗靶点提供一种新的策略。
Abstract
The emergence of 5-Fluorouracil (5-FU) resistance is the barrier to effective clinical outcomes for colorectal cancer (CRC) patients. Autophagy was found to be involved in protecting tumor cells from 5-FU. However, the specific role of autophagy-related genes in CRC 5-FU resistance remains unclear. In this study, HSPB8 among 34 differentially expressed ARGs in CRC was identified to be the hub ARGs in 5-FU resistant which was down-regulated in CRC samples when compared with normal samples but up-regulated in CRC samples with relatively higher lymphatic invasion, later stages and poor prognosis of CRC. Mechanistic analysis demonstrated that due to the recruitment of CAFs, HSPB8 expression was enhanced in CRC cells so that HSPB8 could act together with its co-chaperone BAG3 in autophagy drived 5-FU resistance. Furthermore, the augmented expression level of HSPB8 was found to be significantly correlated to the immune cell infiltration such as Treg cells, macrophages, monocyte and dendritic cells and so on. Our results suggested CAFs driving HSPB8 induced CRC 5-FU resistance by promoting tumor autophagy would provide a new strategy in seeking potential CRC therapeutic target.

https://www.sciencedirect.com/science/article/pii/S2405844022003218