Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China.
Department of General Surgery, Gaochun Branch, Drum Tower Hospital Affiliated to Nanjing University, Nanjing 211300, China.
Acta Biochim Biophys Sin (Shanghai). 2021 Apr 15;53(5):612-619. doi: 10.1093/abbs/gmab032.
Recently, the combined use of FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine plus nab-paclitaxel has significantly improved the prognosis of patients with pancreatic cancer. However, there is still a high proportion of patients who develop metastatic pancreatic cancer in the course of chemotherapy or within a short period after chemotherapy. Previous reports have shown that chemotherapy-driven cytokine storms or the direct effects of certain chemotherapeutics on stromal and/or immune cells collectively change the microenvironment of the primary tumor, thus indirectly promoting metastasis. However, the mechanism underlying chemotherapy-induced metastasis in the course of chemotherapy, and afterwards, remains elusive in pancreatic cancer. In the present study, we aimed to determine the expression of CCL26 in the pancreatic cancer-associated fibroblasts (CAFs) after nab-paclitaxel treatment and to explore the role of CCL26 in the pancreatic adenocarcinoma (PDAC) invasion. Our results showed that nab-paclitaxel increased CCL26 mRNA and protein expression levels in a dose- and time-dependent manner. Subsequently, PDAC cell lines were treated with recombinant CCL26 for 48 h. The transwell migration assay showed that recombinant CCL26 enhanced the invasion of PDAC cells. Western blot analysis showed that the protein expression levels of phospho-(p-)PI3K, p-AKT, and p-mTOR were increased by CCL26 in PDAC cells. CCL26 expressions in 95 PDAC tissues and adjacent normal tissues were evaluated using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. CCL26 was found to be overexpressed in PDAC samples, and upregulated CCL26 expression was significantly associated with advanced perineural invasion, lymph node metastasis, and poor differentiation. In summary, our results showed that nab-paclitaxel increased the expression of CCL26 in CAFs, and CCL26 enhanced the invasive potential of pancreatic cancer cells by activating the PI3K/AKT/mTOR axis. Thus, CCL26 may be a potential prognostic biomarker for pancreatic cancer.
最近，FOLFIRINOX（亚叶酸钙和氟尿嘧啶加伊立替康和奥沙利铂）和吉西他滨加 nab-紫杉醇的联合使用显著改善了胰腺癌患者的预后。然而，仍有相当一部分患者在化疗过程中或化疗后短期内发展为转移性胰腺癌。先前的报告表明，化疗驱动的细胞因子风暴或某些化疗药物对基质和/或免疫细胞的直接作用共同改变了原发肿瘤的微环境，从而间接促进了转移。然而，在胰腺癌化疗过程中以及之后，化疗诱导转移的机制仍不清楚。在本研究中，我们旨在确定 nab-紫杉醇处理后胰腺癌相关成纤维细胞（CAFs）中 CCL26 的表达，并探讨 CCL26 在胰腺腺癌（PDAC）侵袭中的作用。我们的结果表明，nab-紫杉醇以剂量和时间依赖的方式增加了 CCL26 mRNA 和蛋白的表达水平。随后，用重组 CCL26 处理 PDAC 细胞系 48 小时。Transwell 迁移实验表明，重组 CCL26 增强了 PDAC 细胞的侵袭。Western blot 分析表明，CCL26 增加了 PDAC 细胞中磷酸化（p-）PI3K、p-AKT 和 p-mTOR 的蛋白表达水平。使用逆转录定量聚合酶链反应和免疫组织化学评估了 95 例 PDAC 组织和相邻正常组织中的 CCL26 表达。发现 CCL26 在 PDAC 样本中过表达，上调的 CCL26 表达与神经周围浸润、淋巴结转移和低分化显著相关。总之，我们的结果表明，nab-紫杉醇增加了 CAFs 中 CCL26 的表达，CCL26 通过激活 PI3K/AKT/mTOR 轴增强了胰腺癌细胞的侵袭能力。因此，CCL26 可能是胰腺癌的一个潜在预后生物标志物。
