| Purpose.Perineural invasion(PNI)has emerged as a key pathological feature and be considered as a poor prognostic factor in cervical cancer,but the mechanism is still unclear.Nerve-sparing radical hysterectomy(NSRH),that is C1 surgery(Q-M classification),may reduce postoperative bladder,rectal,and sexual dysfunction.However,clinical guidelines clearly point out that PNI is a contraindication of C1 surgery for cervical cancer,and C1 surgery is associated with the risk of postoperative recurrence.Although preoperative imaging and intraoperative freezing examination are helpful for the detection of PNI,their value is limited and cannot guide the selection of surgical methods in time.Diagnosis of PNI still depends on postoperative pathology.This study attempts to explore the role of Schwann cells in cervical cancer PNI,to balance the pros and cons of postoperative quality of life and prognosis for gynecologists to choose the appropriate surgical methods,and open avenues for future treatment.Methods.We selected The Cancer Genome Atlas(TCGA)database.The TCGA database contains not only the multi-omics data of tumor patients,but also the diagnostic pathological images of patients.These images contain sections of tumor tissue large enough(approximately 2cm×2cm)to be used to fully quantify PNI status within tumor tissue.We first downloaded the H&E staining histopathological images(diagnostic)of all patients with cervical cancer from the TCGA database,and then evaluated the PNI status of all the pathological images.Finally,all cervical cancer patients were divided into PNI(+)group and PNI(-)group,the incidence of cervical cancer PNI was calculated,the relationship between PNI status and prognosis of patients was analyzed,and the differentially expressed genes(DEGs)of the two groups were compared.Known PNI-related genes were excluded through literature search.Combined with the expression pattern of differential genes in cervical cancer and the relationship between patients’ prognosis,we further screened candidate PNI-related genes as the object of this study.Meanwhile,immunohistochemical staining,immunofluorescence staining,m RNA sequencing,3D co-culture system,Western blotting and other methods were used to investigate the underlying molecular mechanisms.Results.1.Evaluation results: PNI(+)cervical cancer patients,a total of 40 cases;PNI(-)cervical cancer patients,a total of 229 cases,the incidence of PNI was about14.9%.Survival analysis showed that PNI(+)cervical cancer patients has a worse disease-free survival(DFS),Hazard ratio(HR)is equal to 2.456,that is,PNI(+)cervical cancer patients is associated with poor prognosis.2.There were 85 up-regulated DEGs in the PNI(+)cervical cancer group.Then,Top3 nervous system-related genes among up-regulated DEGs in patients with PNI(+)were further analyzed.After excluding one of the known studied genes,we selected the secretory gene ADCYAP1(log2 fold-change 1.95,P < 0.0001)among the remaining two genes.ADCYAP1 gene,encodes pituitary adenylate cyclase-activating polypeptide(PACAP),was studied in our research.3.Immunohistochemistry of human cervical cancer tissues showed that PACAP was mainly located on tumor cells around the invaded nerves,and the expression intensity of PACAP of PNI(+)group was higher than that of PNI(-)group.4.Schwann cells could up-regulate the levels of GFAP and Vimentin after treating with recombinant PACAP(r PACAP),suggesting that PACAP could activate the Schwann cells into dedifferentiated subtype.5.Activated Schwann cells promoted tumor metastasis or remodeled the tumor microenvironment by secreting FGF17(fibroblast growth factor 17),Cathepsin S(Cathepsin S)and MMP-12(matrix metalloproteinase 12).Conclusion.The high expression of PACAP was positively correlated with PNI of cervical cancer.Specifically,tumor-derived PACAP could promote the occurrence of cervical cancer PNI by activating Schwann cells to produce chemokine FGF17 and changing tumor microenvironment through secretion of Cathepsin S and MMP-12. |
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