Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, People's Republic of China.
Guangdong cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, People's Republic of China.
Mol Cancer. 2022 Jan 19;21(1):24. doi: 10.1186/s12943-022-01501-3.
Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC.
circRNA sequencing and quantitative real-time PCR (qRT-PCR) were utilized to screen CAF-specific circRNAs. The effects of CAF circFARP1 expression on GEM resistance in tumor cells were assessed in vitro and in vivo. RNA-seq, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were used to screen the downstream target and underlying mechanism of circFARP1.
circFARP1 (hsa_circ_0002557), a CAF-specific circRNA, was positively correlated with GEM chemoresistance and poor survival in an advanced PDAC cohort. Silencing or overexpressing circFARP1 in CAFs altered the ability of CAFs to induce tumor cell stemness and GEM resistance via leukemia inhibitory factor (LIF). Mechanistically, we found that circFARP1 directly binds with caveolin 1 (CAV1) and blocks the interaction of CAV1 and the E3 ubiquitin-protein ligase zinc and ring finger 1 (ZNRF1) to inhibit CAV1 degradation, which enhances LIF secretion. In addition, circFARP1 upregulated LIF expression by sponging miR-660-3p. Moreover, high circFARP1 levels were positively correlated with elevated serum LIF levels in PDAC and poor patient survival. Decreasing circFARP1 levels and neutralizing LIF significantly suppressed PDAC growth and GEM resistance in patient-derived xenograft models.
The circFARP1/CAV1/miR-660-3p/LIF axis is critical for CAF-induced GEM resistance in PDAC. Hence, circFARP1 may be a potential therapeutic target for PDAC.
癌症相关成纤维细胞（CAFs）在胰腺导管腺癌（PDAC）中对吉西他滨（GEM）耐药起着关键作用。然而，CAFs 促进化疗耐药的潜在机制尚未得到探索。在这里，我们研究了 circRNA 在 CAF 诱导的 PDAC 中 GEM 耐药中的作用。
使用 circRNA 测序和实时定量 PCR（qRT-PCR）筛选 CAF 特异性 circRNA。在体外和体内评估 CAF 中 circFARP1 的表达对肿瘤细胞 GEM 耐药的影响。使用 RNA 测序、RNA 下拉、RNA 免疫沉淀和荧光素酶报告基因检测筛选 circFARP1 的下游靶标和潜在机制。
circFARP1（hsa_circ_0002557），一种 CAF 特异性 circRNA，与高级 PDAC 队列中 GEM 化疗耐药和不良预后呈正相关。在 CAFs 中沉默或过表达 circFARP1 可改变 CAFs 通过白血病抑制因子（LIF）诱导肿瘤细胞干性和 GEM 耐药的能力。在机制上，我们发现 circFARP1 可直接与窖蛋白 1（CAV1）结合，并阻断 CAV1 和 E3 泛素蛋白连接酶锌指和环指 1（ZNRF1）的相互作用，抑制 CAV1 降解，从而增强 LIF 分泌。此外，circFARP1 通过海绵吸附 miR-660-3p 上调 LIF 表达。此外，在 PDAC 中，circFARP1 水平升高与血清 LIF 水平升高呈正相关，与患者预后不良相关。降低 circFARP1 水平和中和 LIF 可显著抑制患者来源的异种移植模型中的 PDAC 生长和 GEM 耐药。
circFARP1/CAV1/miR-660-3p/LIF 轴在 CAF 诱导的 PDAC 中 GEM 耐药中起着关键作用。因此，circFARP1 可能是 PDAC 的潜在治疗靶点。
