Dedifferentiated Schwann cells promote perineural invasion mediated by the PACAP paracrine signalling in cervical cancer.

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.

Esthetics Effect and the Modified Placement of Robotic-Assisted Single-Site Laparoscopic Gynecologic Surgery by Common Robotic Instruments and LAGIS Single-Site Port.

OBJECTIVES: The accuracy of robotic surgery has been recognized by many doctors, but traditional robotic surgery requires 4-5 puncture holes in the operating area. With the popularization and application of single port laparoscopic surgery, the aesthetic of abdominal incision of robotic surgery has been challenged. How to use the single-site platform to complete robot operation is a new field worthy of our exploration. Here we introduce a kind of technology innovation of robot-assisted single-site laparoscopic surgery through common robotic equipment and LAGIS single-site port. METHODS: From November 2018 to March 2019, 20 patients with cervical cancer or endometrial cancer admitted to the minimally invasive gynecological group were included. Single-hole robotic surgery was successfully performed in all 20 patients, with no additional assisted puncture and no conversion to laparotomy. The operation time of patients, intraoperative bleeding volume and hospitalization time were recorded and compared. Besides, the Intraoperative complications were observed and analyzed. RESULTS AND CONCLUSIONS: By comparison, we can find that the effect of this innovative single-hole robotic surgery is significantly better than that of traditional single-hole laparoscopy.

Robotic single-site surgery versus laparoendoscopic single-site surgery in early-stage endometrial cancer: a case-control study.

INTRODUCTION: Laparoendoscopic single-site surgery (LESS) can reduce the limited invasiveness of conventional laparoscopy while providing superior cosmetic results. Robotic single-site surgery (RSSS) can overcome this shortcoming to a certain extent. AIM: To evaluate the advantages of RSSS in treating early-stage endometrial cancer by comparing RSSS with LESS. MATERIAL AND METHODS: From January 2018 to August 2018, patients diagnosed with endometrial cancer from endometrial curettage and imaging studies were selected for this prospective cohort study, with 22 undergoing RSSS and 18 undergoing LESS. All surgical procedures were performed using the conventional da Vinci Si surgical system with the Lagiport single port or a conventional laparoendoscopic instrument with the Lagiport single port. Operative time was recorded electronically. Intraoperative parameters and postoperative parameters were recorded and further analyzed. RESULTS: The operation was successfully completed, and a pure single-point approach was adopted. There were no laparotomy or intraoperative complications. Compared with the LESS group, the RSSS group had significantly longer pre-surgical time, significantly lower median operation time, significantly lower median blood loss, and significantly lower vaginal cuff closure time. The median length of hospital stay in the RSSS group was significantly lower than that in the LESS group. There was no significant difference in the incidence of early and late complications between the two groups. No recurrence events were observed in either the RSSS or the LESS group. CONCLUSIONS: RSSS is feasible and safe in patients with early-stage endometrial cancer. RSSS can reduce operating time, blood loss and length of hospital stay compared with LESS.

Stress Hormones: Emerging Targets in Gynecological Cancers.

In the past decade, several discoveries have documented the existence of innervation in ovarian cancer and cervical cancer. Notably, various neurotransmitters released by the activation of the sympathetic nervous system can promote the proliferation and metastasis of tumor cells and regulate immune cells in the tumor microenvironment. Therefore, a better understanding of the mechanisms involving neurotransmitters in the occurrence and development of gynecological cancers will be beneficial for exploring the feasibility of using inexpensive ß-blockers and dopamine agonists in the clinical treatment of gynecological cancers. Additionally, this article provides some new insights into targeting tumor innervation and neurotransmitters in the tumor microenvironment.

Mechanism of hydrogen on cervical cancer suppression revealed by high­throughput RNA sequencing.

Cervical cancer is considered one of the diseases with the highest mortality among women and with limited treatment options. Hydrogen (H2) inhalation has been reported to have a variety of tumor­suppressive effects, but the exact mechanism remains unclear. In the present study, HeLa cervical cancer cells and HaCaT keratinocytes treated with H2, and a HeLa xenograft mouse model subjected to H2 inhalation were established. TUNEL, Cell Counting Kit­8 and Ki67 staining assays were used to detect cell apoptosis and proliferation. Oxidative stress was determined according to the levels of reactive oxygen species, malondialdehyde and superoxide dismutase. Tumor growth was recorded every 3 days, and the excised tumors were stained with hematoxylin and eosin. High­throughput RNA sequencing and subsequent Gene Ontology (GO) enrichment analysis were performed in HeLa­treated and un­treated HeLa cells. The expression of hypoxia­inducible factor (HIF)­1α and NF­κB p65 was verified by western blotting, immunohistochemistry and reverse transcription­quantitative PCR. The results revealed an increased apoptosis rate, and reduced cell proliferation and oxidative stress in H2­treated HeLa cells but not in HaCaT cells. Similarly, decreased tumor growth and cell proliferation, and enhanced cell apoptosis were observed in H2­treated HeLa tumors. RNA sequencing and GO analysis suggest that downregulated HIF1A (HIF­1α mRNA) and RelA (NF­κB p65) levels, and reduced NF­κB signaling were associated with the antitumor effect of H2. Finally, decreased HIF­1α and NF­κB p65 expression both at the transcriptional and translational levels were observed in H2­treated HeLa cells and in HeLa­derived tumors. In conclusion, the present study reveals a novel mechanism of H2 against cervical cancer, which may serve as a potential therapeutic target in clinical practice.

A Comparative Analysis of Robotic Single-Site Surgery and Laparoendoscopic Single-Site Surgery as Therapeutic Options for Stage IB1 Cervical Squamous Carcinoma.

PURPOSE: To compare perioperative outcomes between robotic single-site surgical technique and conventional laparoendoscopic single-site surgical technique. METHODS: This was a retrospective cohort study involving 67 patients who received robotic single-site surgery or laparoendoscopic single-site surgery for the treatment of stage IB1 cervical squamous carcinoma. The robotic single-site radical hysterectomy technique combined with pelvic lymph node dissections were performed in 32 patients while the laparoendoscopic single-site radical hysterectomy technique combined with pelvic lymph node dissections were performed in 35 patients. RESULTS: The enrolled patients had been diagnosed with stage IB1 cervical squamous carcinoma. The perioperative outcomes were mean age (51.63±8.32 years in the lymph node dissection (RSS group) and 53.14±8.14 years in the lymph node dissection (LESS group), p=0.453); BMIs (23.76±2.72 in the RSS group and 23.46±2.28 in the LESS group, p=0.629); shorter operative times (223.56±15.43 min in the RSS group and 248.61±20.89 min in the LESS group, p<0.01) and less estimated blood loss (217.25±16.77 mL in the RSS group and 294.74±24.00 mL in the LESS group, p<0.01). None of the study participants exhibited postoperative pain. There were no statistically significant differences in the length of hospital stay (p=0.865), perioperative complications (p=0.602), duration of closure and removal of catheter (p=0.518) as well as in pathological diagnoses between the two groups. CONCLUSION: Robotic single-site surgery can be used in the treatment of early stage cervical cancer as it exhibits acceptable operative times and perioperative outcomes. This surgical technique is feasible and safe.

Deregulation of angiopoietin-like 4 slows ovarian cancer progression through vascular endothelial growth factor receptor 2 phosphorylation.

BACKGROUND: As a tissue-specific proangiogenic or antiangiogenic agent, angiopoietin-like 4 (ANGPTL4) has recently gained attention in many diseases, such as metabolic syndrome, cardiovascular disease and cancer. However, the roles of ANGPTL4 in angiogenesis and tumor growth in epithelial ovarian cancer, the most lethal gynecologic malignancy, remain unclear. OBJECTIVE: To identify a novel mechanism of ANGPTL4 inhibition in epithelial ovarian cancer. METHODS: Western blot, quantitative reverse transcription PCR, and immunofluorescence analyses were applied to evaluate ANGPTL4 expression in ovarian cancer cell lines. Cell proliferation, migration, and invasion were investigated through 5-ethynyl-2'-deoxyuridine (EdU) incorporation, CCK-8 and Transwell assays. The expression of epithelial-mesenchymal transition (EMT)-related proteins in ovarian cancer cells and tumor-bearing mice was evaluated. CD31 staining was used to identify tumor angiogenesis. Immunoprecipitation was performed to examine the regulatory relationship between ANGPTL4 and the vascular endothelial growth factor receptor 2 (VEGFR2)/vascular endothelial (VE)-cadherin/Src complex. VEGFR2 phosphorylation at Y949 and VE-cadherin expression were assessed by western blotting. Inactivation of VEGFR2 Y949 phosphorylation was achieved in a MISIIR-TAg VEGFR2Y949F/Y949F mouse model. RESULTS: Here, we demonstrated that ANGPTL4 was overexpressed in A2780 and CAOV3 ovarian cancer cells. In vitro assays indicated that inhibition of ANGPTL4 by lentiviral small interfering RNA does not alter ovarian cancer cell proliferation, migration, invasion, and EMT, while ANGPTL4 silencing exhibited significant inhibitory effects on tumor angiogenesis, growth, and metastasis in vivo. Immunoprecipitation analysis showed that suppression of ANGPTL4 was accompanied by dissociation of the VEGFR2/VE-cadherin/Src complex and phosphorylation of VEGFR2 Y949 in A2780 and CAOV3 ovarian tumors. Inactivation of VEGFR2 Y949 phosphorylation in MISIIR-TAg VEGFR2Y949F/Y949F mice abolished all tumor-suppressive effects of ANGPTL4 inhibition in spontaneous ovarian carcinoma. CONCLUSIONS: Overall, our results indicate that ANGPLT4 silencing delays tumor progression in specific types of ovarian cancer and may be a potential target for individualized treatment of ovarian cancer.

Roles of metformin-mediated girdin expression in metastasis of epithelial ovarian cancer.

Antimetastatic effect of Metformin has been documented in epithelial ovarian cancer (EOC). Presently, we investigated the regulatory mechanism of Metformin in EOC metastasis. First, Girdin was significantly enhanced in EOC tumorous tissues and cell lines. Seconded, knockdown of Girdin significantly suppressed EOC cell viability, migration, and invasion, while upregulation of Girdin produced the opposite effects in vitro and facilitated lung metastasis in EOC cell xenograft in vivo. In addition, we confirmed that the inhibitory effect of Metformin on Girdin expression. Mechanistically, the oncogenic effects of Girdin could be reversed by LY294002 (an AKT pathway inhibitor) and Metformin. These results suggested that Metformin attenuated EOC metastasis through Girdin and targeting Girdin may be a promising therapeutic strategy for EOC in the future.

Identification of two molecular subtypes of dysregulated immune lncRNAs in ovarian cancer.

Long non-coding RNA (lncRNA) has increasingly been identified as a key regulator in pathologies such as cancer. Multiple platforms were used for comprehensive analysis of ovarian cancer to identify molecular subgroups. However, lncRNA and its role in mapping the ovarian cancer subpopulation are still largely unknown. RNA-sequencing and clinical characteristics of ovarian cancer were acquired from The Cancer Genome Atlas database (TCGA). A total of 52 lncRNAs were identified as aberrant immune lncRNAs specific to ovarian cancer. We redefined two different molecular subtypes, C1(188) and C2(184 samples), in "iClusterPlus" R package, among which C2 grouped ovarian cancer samples have higher survival probability and longer median survival time (P <0.05) with activated IFN-gamma response, Wound Healing and Cytotoxic lymphocytes signal; 456 differentially expressed genes were acquired in C1 and C2 subtypes using limma (3.40.6) package, among which 419 were up-regulated and 37 were down-regulated, in TCGA dataset. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis revealed that these genes were actively involved in ECM-receptor interaction, PI3K-Akt signaling pathway interaction KEGG pathway. Compared with the existing immune subtype, the Cluster2 sample showed a substantial increase in the proportion of the existing C2 immune subtype, accounting for 81.37%, which was associated with good prognosis. Our C1 subtype contains only 56.49% of the existing immune C1 and C4, which also explains the poor prognosis of C1. Furthermore, 52 immune-related lncRNAs were used to divide the TCGA-endometrial cancer and cervical cancer samples into two categories, and C2 had a good prognosis. The differentially expressed genes were highly correlated with immune-cell-related pathways. Based on lncRNA, two molecular subtypes of ovarian cancer were identified and had significant prognostic differences and immunological characteristics.