Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Acta Pharmacol Sin. 2023 Jan;44(1):178-188. doi: 10.1038/s41401-022-00927-1. Epub 2022 Jun 8.
Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.
维生素 D 受体 (VDR) 在癌相关成纤维细胞 (CAFs) 中的激活被认为与多种人类恶性肿瘤的肿瘤进展和化疗耐药有关。然而，VDR 在 CAF 诱导的胃癌 (GC) 细胞化疗耐药中的作用仍不清楚。在这项研究中，我们首先对包括 88 对 GC 和正常黏膜样本的组织微阵列进行了免疫组织化学分析，提供了临床证据表明 VDR 主要在胃黏膜细胞中表达，但在 CAFs 中几乎不可见，VDR 表达与恶性临床表型和晚期呈负相关，VDR 低表达提示 GC 患者总体生存率差。在原代 CAFs 和癌细胞的共培养系统中，我们表明 VDR 配体卡泊三醇 (Cal，500 nM) 处理 HGC-27 和 AGS GC 细胞可显著抑制 CAF 诱导的奥沙利铂耐药。通过 RNA 测序和人细胞因子抗体阵列，我们证明了 CAFs 分泌的 IL-8 通过激活 PI3K/AKT 通路在 GC 中诱导奥沙利铂耐药，而 Cal 处理大大减弱了 CAF 衍生的 IL-8 对 GC 细胞的肿瘤支持作用。总之，这项研究验证了 VDR 在 GC 组织中的特定定位，并表明激活 VDR 通过阻断 PI3K/Akt 信号通路可消除 CAF 衍生的 IL-8 介导的 GC 中的奥沙利铂耐药，提示维生素 D 补充可能是增强 GC 中化疗抗肿瘤作用的一种潜在策略。
