Involvement of DPP3 in modulating oncological features and oxidative stress response in esophageal squamous cell carcinoma.

Resistance to therapy in esophageal squamous cell carcinoma (ESCC) is a critical clinical problem and identification of novel therapeutic targets is highly warranted. Dipeptidyl peptidase III (DPP3) is a zinc-dependent aminopeptidase and functions in the terminal stages of the protein turnover. Several studies have reported overexpression and oncogenic functions of DPP3 in numerous malignancies. The present study aimed to determine the expression pattern and functional role of DPP3 in ESCC. DPP3 expression was assessed in normal and tumor tissues using quantitative real-time (qRT)-PCR and corroborated with ESCC gene expression datasets from Gene Expression Omnibus (GEO) and The cancer genome atlas (TCGA). DPP3 stable knockdown was performed in ESCC cells by shRNA and its effect on cell proliferation, migration, cell cycle, apoptosis, and activation of nuclear factor erythroid 2-related factor 2 (NRF2) pathway was assessed. The results suggested that DPP3 is overexpressed in ESCC and its knockdown leads to reduced proliferation, increased apoptosis, and inhibited migration of ESCC cells. Additionally, DPP3 knockdown leads to down-regulation of the NRF2 pathway proteins, such as NRF2, G6PD, and NQO1 along with increased sensitivity toward oxidative stress-induced cell death and chemotherapy. Conclusively, these results demonstrate critical role of DPP3 in ESCC and DPP3/NRF2 axis may serve as an attractive therapeutic target against chemoresistance in this malignancy.

Endometrial stromal cell inflammatory phenotype during severe ovarian endometriosis as a cause of endometriosis-associated infertility.

RESEARCH QUESTION: Do endometrial stromal cells from primary infertile patients with severe ovarian endometriosis display differential secretory profiles of inflammation-associated cytokines during the implantation window that may cause infertility? DESIGN: Forty-eight cytokines were measured in conditioned medium of isolated endometrial stromal cells obtained from primary infertile patients without endometriosis (control group, n = 12) or with stage IV ovarian endometriosis (ovarian endometriosis group, n = 14) using multiplex assays. Key cytokines showing differential secretory profiles were validated using Western immunoblotting. Cellular phenotypic validation was carried out in vitro by comparing proliferation and migration capacity between control (n = 6) and ovarian endometriosis (n = 7) groups. RESULTS: CCL3, CCL4, CCL5, CXCL10, FGF2, IFNG, IL1RN, IL5, TNFA, and VEGF could be detected only in the conditioned media of stromal cells obtained from the ovarian endometriosis group. Among other cytokines detected in the conditioned media of both groups, CCL2 (P = 0.0018), CSF3 (P = 0.0017), IL1B (P = 0.0066), IL4 (P = 0.036), IL6 (P = 0.0039) and IL13 (P = 0.036) were found to be higher, whereas the concentration of IL18 was lower (P = 0.023) in the ovarian endometriosis group. Concentrations of CCL2, IL1B, IL4 and IL13 in conditioned medium reflected significant diagnostic performance for predicting ovarian endometriosis. Cellular phenotypic validation in vitro revealed an enhanced proliferative phenotype (P = 0.046) with no change in cell migratory capacity of endometrial stromal cells from the ovarian endometriosis group. CONCLUSIONS: Endometrial stromal cells derived from severe ovarian endometriosis samples displayed a hyperinflammatory and hyperproliferative bias in the endometrial stroma during the 'window of implantation' putatively causing loss of fecundability.