Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism. CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis, thus suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7 SW620-CRHR2+ and miR-7 HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing. CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli.

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BackgroundComplex ventral incisional hernia repair represents a challenging clinical condition in which biologically derived graft reinforcement is often utilized, but little long-term data inform that decision. Urinary bladder matrix (UBM) has shown effectiveness in diverse clinical settings as durable reinforcement graft material, but it has not been studied over a long term in ventral incisional hernia repair. This study evaluates the clinical, radiographic, and histological outcome of complex incisional hernia repair using UBM reinforcement with 12–70 months of follow-up.MethodsA single-arm, retrospective observational study of all ventral incisional hernia repairs utilizing UBM reinforcement over a 6-year time frame by a single surgeon was performed. Patients were assessed in long-term follow-up clinically and with the Carolina Comfort Scale. A subset of patients was assessed with abdominal wall ultrasound or CT scan. Three patients had abdominal wall fascial biopsies years after the incisional hernia repair with UBM graft, and the histology is analyzed.Results64 patients underwent repair of complex incisional hernias with UBM graft reinforcement by a single surgeon. 42 patients had concomitant procedures including large or small bowel resection, excision of infected mesh, evacuation of abscess or hematoma, cholecystectomy, or panniculectomy with abdominoplasty. 16 patients had ostomies at the time of repair. Median follow-up time is 36 months, with a range of 12–70 months. Nine patients (14%) have required surgical repair of a recurrent hernia, and a tenth patient has a recurrence that is managed non-surgically, for a total recurrence rate of 15.6% over the entire time frame. Median time to recurrence was 32 months, and a Kaplan–Meier freedom from recurrence curve is depicted. 28 patients have undergone ultrasound or CT assessments of the abdominal wall which demonstrate radiographic fascial integrity 12–70 months after repair. Three patients have been re-explored for unrelated reasons in the years following ventral incisional hernia repair with UBM, and full thickness fascial biopsies demonstrate a robust remodeling response histologically similar to native myofascial tissue. No patients have developed graft infection, fistulization to the graft, or required graft explantation. Carolina Comfort Scale assessment of 45 patients 3 years after the repair averaged 16 out of a possible 115.ConclusionIn 64 patients undergoing complex ventral incisional hernia repair with UBM reinforcement, all have experienced successful resolution of complex clinical conditions and 15.6% of these repairs have recurred at a median follow-up of 3 years. Three full-thickness biopsies of the repaired fascia years later shed light on a promising remodeling response which may signal strength and durability comparable to native fascia.

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