Department of Obstetrics and Gynecology, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
Department of Gynecology, The People's Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen, China.
J Cell Mol Med. 2023 Dec;27(23):3692-3705. doi: 10.1111/jcmm.17897. Epub 2023 Oct 13.
Perineural invasion (PNI) has emerged as a key pathological feature and be considered as a poor prognostic factor in cervical cancer. However, the underlying molecular mechanisms are largely unknown. Here, PNI status of 269 cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) samples were quantified by using whole-slide diagnostic images obtained from The Cancer Genome Atlas. Integrated analyses revealed that PNI was an indicative marker of poorer disease-free survival for CESC patients. Among the differentially expressed genes, ADCYAP1 were identified. Clinical specimens supported that high expression of PACAP (encoded by ADCYAP1) contributed to PNI in CESC. Mechanistically, PACAP, secreted from cervical cancer cells, reversed myelin differentiation of Schwann cells (SCs). Then, dedifferentiated SCs promoted PNI by producing chemokine FGF17 and by degrading extracellular matrix through secretion of Cathepsin S and MMP-12. In conclusion, this study identified PACAP was associated with PNI in cervical cancer and suggested that tumour-derived PACAP reversed myelin differentiation of SCs to aid PNI.
神经周围侵犯（PNI）已成为宫颈癌的一个关键病理特征，并被认为是预后不良的因素。然而，其潜在的分子机制在很大程度上尚不清楚。本研究使用从癌症基因组图谱获得的全切片诊断图像，对 269 例宫颈鳞状细胞癌和子宫内膜腺癌（CESC）样本的 PNI 状态进行了定量分析。综合分析显示，PNI 是 CESC 患者无病生存的预后不良标志物。在差异表达基因中，发现了 ADCYAP1。临床标本支持 PACAP（由 ADCYAP1 编码）的高表达有助于 CESC 中的 PNI。在机制上，PACAP 由宫颈癌细胞分泌，逆转施万细胞（SCs）的髓鞘分化。然后，去分化的SCs 通过分泌趋化因子 FGF17 和通过分泌组织蛋白酶 S 和 MMP-12 降解细胞外基质来促进 PNI。总之，本研究鉴定出 PACAP 与宫颈癌中的 PNI 相关，并提示肿瘤来源的 PACAP 逆转了 SCs 的髓鞘分化以辅助 PNI。
