Cervical cancer screening by combined cytology and HPV test has reduced the incidence of cervical cancer, but cytological screening lacks a higher sensitivity while HPV testing possesses a lower specificity. Most patients with invasive cervical cancer are treated with radiotherapy. However, insensitivity to radiotherapy leads to poor efficacy. Illumina Methylation EPIC 850k Beadchip was used for genomic screening. We detected methylation of SEPT9 and mRNA expression in different cervical tissues by using methylation-specific PCR and qRT-PCR. Then using CCK8, migration assay, and flow cytometry to detect the biological function and irradiation resistance of SEPT9 in vitro and in vivo. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (CoIP) were used to find the interacting gene with SEPT9. Immunostaining of CD206 in cervical cancer and polarization of macrophages (M2) were evaluated by immunofluorescence and WB. The Cancer Genome Atlas (TCGA) database was used for screening the potential miRNAs induced by SEPT9. Hyper-methylation of SEPT9 detects cervical cancer and normal tissues, normal+CIN1 and CIN2+CIN3+cancer with high sensitivity and specificity (AUC = 0.854 and 0.797, respectively, P < 0.001). The mRNA and protein expression of SEPT9 was upregulated in cervical cancer tissues when compared to para-carcinoma tissues. SEPT9 promotes proliferation, invasion, migration, and influences the cell cycle of cervical cancer. SEPT9 interacted with HMGB1-RB axis increases irradiation resistance. Furthermore, SEPT9 mediated miR-375 via the tumor-associated macrophages (TAMs) polarization, affecting the resistance to radiotherapy in cervical cancer. These findings give us the evidence that SEPT9 methylation could be a biomarker for cervical cancer diagnoses. It promotes tumorigenesis and radioresistance of cervical cancer by targeting HMGB1-RB axis and causes polarization of macrophages by mediating miR-375. We suggest SEPT9 could be a potential screening and therapeutic biomarker for cervical cancer.

Transforming growth factor‐β1 (TGF‐β1) induces stromal fibroblast‐to‐myofibroblast transdifferentiation in the tumor‐stroma interactive microenvironment via modulation of multiple phenotypic and functional genes, which plays a critical role in tumor progression. Up to now, the involvement of micro‐RNAs (miRNAs) and their roles in TGF‐β1‐induced myofibroblast differentiation in tumor‐stroma interaction are unclear. Using quantitative real‐time RT‐PCR, we demonstrated that the expression of micro‐RNA‐21 (miR‐21) was upregulated in activated fibroblasts after treatment with TGF‐β1 or conditioned medium from cancer cells. To determine the potential roles of miR‐21 in TGF‐β1‐mediated gene regulation during myofibroblast conversion, we showed that miR‐21 expression was downregulated by miR‐21 inhibitor and upregulated by miR‐21 mimic. Interestingly, downregulation of miR‐21 with the inhibitor effectively inhibited TGF‐β1‐induced myofibroblast differentiation while upregulation of miR‐21 with a mimic significantly promoted myofibroblast differentiation. We further demonstrated that MiR‐21 directly targeted and downregulated programmed cell death 4 (PDCD4) gene, which in turn acted as a negative regulator of several phenotypic and functional genes of myofibroblasts. Taken together, these results suggested that miR‐21 participated in TGF‐β1‐induced myofibroblast transdifferentiation in cancer stroma by targeting PDCD4.

Recent morphologic and molecular genetic studies have led to a paradigm shift in our conceptualization of the carcinogenesis and histogenesis of pelvic (non-uterine) serous carcinomas. It appears that both low-grade and high-grade pelvic serous carcinomas that have traditionally been classified as ovarian in origin, actually originate, at least in a significant subset, from the distal fallopian tube. Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. In this article, the authors review the evidentiary basis for aforementioned paradigm shift, as well as its potential clinical implications.

MiR-145 inhibits tumor growth and metastasis by targeting metadherin in high-grade serous ovarian carcinoma miR-145 inhibits tumor growth and metastasis by targeting metadherin in high-grade serous ovarian carcinoma

Rationale: Ovarian cancer is a highly lethal gynecological malignancy with common platinum resistance. Lactylation is involved in multiple biological processes. Thus, we explored the role of histone and non-histone lactylation in platinum resistance, providing a potential therapeutic target to overcome platinum resistance in ovarian cancer.