Dampened Regulatory Circuitry of TEAD1/ITGA1/ITGA2 Promotes TGFß1 Signaling to Orchestrate Prostate Cancer Progression.

The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a meta-analysis of multiple PCa cohorts is performed which revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes is associated with tumor progression and worse prognosis. Genomic deletion of both ITGA1 and ITGA2 activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT is induced by enhanced secretion and autocrine activation of TGFß1 and nuclear targeting of YAP1. An unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of α1- and α2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss is associated with aggressive PCa and together with low ITGA1 and ITGA2 expression synergistically impacted PCa prognosis and progression. This study thus demonstrated that loss of α1- and α2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGFß1-driven EMT.

Meta-analysis of prophylactic negative pressure wound therapy for surgical site infections (SSI) in caesarean section surgery.

Introduction: Negative pressure wound therapy (NPWT) has been used in reducing the incidence of surgical site infections (SSIs) and wound complications across various surgical categories. SSIs are a common post-surgical complication following caesarean section (CS) births, making it necessary to use prophylactic interventions to reduce SSI and wound complication incidences. Aim: To conduct an updated meta-analysis on randomized controlled trials (RCTs) comparing SSI incidence and wound complications in women undergoing C-sections receiving NPWT or standard dressings after wound closure. Material and methods: A systematic literature review was conducted using MEDLINE and CENTRAL databases, and clinical trial registries for RCTs that involved NPWT versus standard dressings in participants undergoing C-section procedures. The primary outcome was surgical site infection (SSI) and other wound complications (haematoma, dehiscence, seroma. Results: A total of 11 RCTs were included in the meta-analysis with information from 5,693 patients. A reduction in overall SSI incidence (RR = 0.79, 95% CI: 0.66-0.95, p = 0.01, I2 = 0%) and wound complication rate (RR = 0.86, 0.75 to 0.98, p = 0.02, I2 = 5%) was found with all studies pooled together. Subgroup analyses showed that NPWT did not significantly reduce SSI incidence when stratified by the type of C-section (emergency/elective) whereas the type of NPWT device had a differential effect on SSI reduction, with PICO NPWT systems showing a beneficial effect (RR = 0.72, 0.58 to 0.91, p = 0.006, I2 = 0%) in comparison to the PREVENA closed-incision device (RR = 0.94, 0.68 to 1.29, p = 0.73, I2 = 0%). Conclusions: Prophylactic NPWT is useful in reducing the incidence of SSIs in women undergoing C-sections based on synthesis of results from RCTs in obese women (BMI > 30 kg/m2).

GATA2 co-opts TGFß1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression.

BACKGROUND: Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic genomic event cooperates with inherited germline variants contribute to cancer predisposition and progression. METHODS: We applied integrated genomic and clinical data, experimental models and bioinformatic analysis to identify GATA2 as a highly prevalent metastasis-associated genomic amplification in PCa. Biological roles of GATA2 in PCa metastasis was determined in vitro and in vivo. Global chromatin co-occupancy and co-regulation of GATA2 and SMAD4 was investigated by coimmunoprecipitation, ChIP-seq and RNA-seq assays. Tumor cellular assays, qRT-PCR, western blot, ChIP, luciferase assays and CRISPR-Cas9 editing methods were performed to mechanistically understand the cooperation of GATA2 with SMAD4 in promoting TGFß1 and AR signaling and mediating inherited PCa risk and progression. RESULTS: In this study, by integrated genomics and experimental analysis, we identified GATA2 as a prevalent metastasis-associated genomic amplification to transcriptionally augment its own expression in PCa. Functional experiments demonstrated that GATA2 physically interacted and cooperated with SMAD4 for genome-wide chromatin co-occupancy and co-regulation of PCa genes and metastasis pathways like TGFß signaling. Mechanistically, GATA2 was cooperative with SMAD4 to enhance TGFß and AR signaling pathways, and activated the expression of TGFß1 via directly binding to a distal enhancer of TGFß1. Strinkingly, GATA2 and SMAD4 globally mediated inherited PCa risk and formed a transcriptional complex with HOXB13 at the PCa risk-associated rs339331/6q22 enhancer, leading to increased expression of the PCa susceptibility gene RFX6. CONCLUSIONS: Our study prioritizes causal genomic amplification genes with prognostic values in PCa and reveals the pivotal roles of GATA2 in transcriptionally activating the expression of its own and TGFß1, thereby co-opting to TGFß1/SMAD4 signaling and RFX6 at 6q22 to modulate PCa predisposition and progression.

CircCOL5A1 inhibits proliferation, migration, invasion, and extracellular matrix production of keloid fibroblasts by regulating the miR-877-5p/EGR1 axis.

BACKGROUND: Circular RNA (circRNA) has been proved to mediate the biological functions of fibroblasts to participate in the regulation of keloid formation. However, the role of circCOL5A1 in keloid formation remains to be further confirmed. METHODS: Primary keloid fibroblasts were isolated form keloid tissues. The expression of circCOL5A1, microRNA (miR)- 877-5p, and early growth response 1 (EGR1) were determined by quantitative real-time PCR. Transfection experiments were carried out to explore the effects of circCOL5A1, miR-877-5p, and EGR1 on cell functions. Cell proliferation, migration, invasion and apoptosis were detected using cell counting kit 8 assay, colony formation assay, transwell assay and flow cytometry. The protein levels of apoptosis markers, extracellular matrix (ECM) markers and EGR1 were measured by western blot analysis. The mechanism of circCOL5A1 was confirmed by RNA pull-down assay, dual-luciferase reporter assay and RIP assay. RESULTS: Our data showed that circCOL5A1 was upregulated in keloid tissues and fibroblasts. Silencing of circCOL5A1 had an inhibition effect on proliferation, migration, invasion and ECM production, while had a promotion effect on apoptosis in keloid fibroblasts. MiR-877-5p could be sponged by circCOL5A1, and its overexpression could repress the biological functions of keloid fibroblasts. The rescue experiments showed that miR-877-5p inhibitor could reverse the suppressive effect of circCOL5A1 knockdown on the biological functions of keloid fibroblasts. In addition, EGR1 was a target of miR-877-5p, and its expression was positively regulated by circCOL5A1. The inhibition effect of miR-877-5p on the biological functions of keloid fibroblasts could be abolished by EGR1 overexpression. CONCLUSION: In summary, circCOL5A1 facilitates keloid fibroblast proliferation, migration, invasion and ECM production through the miR-877-5p/EGR1 axis, thereby potentially promoting keloid formation.

LncRNA MSC-AS1, as an oncogene in melanoma, promotes the proliferation and glutaminolysis by regulating the miR-330-3p/ YAP1 axis.

Melanoma is a kind of aggressive skin neoplasms with high mortality. The purpose of this present research was to investigate the effects and potential mechanisms of long-noncoding RNA (lncRNA) MSC antisense RNA 1 (MSC-AS1) in melanoma. MSC-AS1, miR-330-3p and YAP1 expression levels in melanoma tissues and cells were assessed by quantitative real-time polymerase chain reaction. Melanoma cells were evaluated using cell count kit-8, clone formation and ELISA in vitro . The relationship among MSC-AS1, YAP1 and miR-330-3p was validated by pull-down and luciferase reporter assays. Finally, the role of MSC-AS1 in vivo was determined by the xenograft model. Results showed that lncRNA MSC-AS1 was upregulated in melanoma tissues and cells. High expression of MAS-AS1 was positively correlated with a poor prognosis. Pull-down and luciferase reporter demonstrated that miR-330-3p specifically binds directly to YAP1 and MSC-AS1, respectively. MSC-AS1 promoted the expression of YAP1 by downregulating miR-330-3p. Functional experiments suggested that knockdown of MSC-AS1 suppressed the proliferation of melanoma cells and decreased the levels of glutamine, glutamate and α-ketoglutarate, glutaminase and glutamine transporter alanine-serine-cysteine transporter 2. Upregulation of miR-330-3p alleviated the promotion effect of MSC-AS1 overexpression on the proliferation and glutaminolysis of melanoma cells. The above changes could be reversed by YAP1 overexpression. In addition, knockdown of MSC-AS1 dramatically restrained the growth of melanoma cells in xenograft model. In conclusion, our results revealed that MSC-AS1 facilitated the proliferation and glutaminolysis of melanoma cells by regulating miR-330-3p/ YAP1 pathway, suggesting that MSC-AS1 could provide a new idea for the treatment of melanoma.

GBP2 Is a Favorable Prognostic Marker of Skin Cutaneous Melanoma and Affects Its Progression via the Wnt/ß-catenin Pathway.

OBJECTIVE: Skin cutaneous melanoma (SKCM) is a common cutaneous malignant tumour. This study explored the expression and the downstream regulation mechanism of guanylate binding protein 2 (GBP2), an interferon (IFN)-induced protein, in SKCM. METHODS: Western blot was employed to verify the expression of SBP2 and its downstream Wnt/ß-catenin pathway-related proteins. We studied the relationship between GBP2 and the SKCM prognosis through database analysis. In vitro, gain-and-loss-of function experiments were conducted in SKCM cells. Cell viability was monitored by the cell counting kit-8 (CCK8) assay, the colony formation assay detected cell proliferation, and apoptosis was verified by flow cytometry. Transwell assay was conducted to test cell invasion and migration, while Western blot was employed to monitor the epithelial-mesenchymal transition (EMT) of SKCM cells. RESULTS: The GBP2 expression in SKCM cells and tissues was lower than normal cells and tissues. GBP2 overexpression inhibited SKCM cell proliferation, migration, invasion, and EMT and promoted cell apoptosis. In contrast, the GBP2 knockdown had the reverse effect. Mechanically, Wnt/ß-catenin was inactivated by GBP2 overexpression and was enhanced by GBP2 knockdown. Drug activation of Wnt/ß-catenin significantly attenuated the malignant phenotypic inhibition induced by GBP2 up-regulation in SKCM cells. CONCLUSION: GBP2 exerts anti-tumour effects by inhibiting the Wnt/ß-catenin pathway in SKCM and is related to a favourable prognosis.

Organ-associated pseudosarcomatous myofibroblastic proliferation with ossification in the lower pole of the kidney mimicking renal pelvic carcinoma: A case report.

BACKGROUND: Organ-associated pseudosarcomatous myofibroblastic proliferation (PMP) is a very rare disorder. In the urogenital tract, PMP preferentially involves the urinary bladder; kidney involvement is rare. Here, we report a rare case of PMP with ossification in the lower pole of the kidney, which mimics urothelial carcinoma or an osteogenic tumor. CASE SUMMARY: A Chinese man was admitted to our hospital due to intermittent hematuria for more than 1 mo. Enhanced renal computed tomography revealed a mass in the left renal pelvis and upper ureter. The preoperative clinical diagnosis was renal pelvic carcinoma, determined by imaging examination and biopsy. After a standard preparation for surgery, the patient underwent retroperitoneoscopic radical nephroureterectomy. The operative findings were an extensive renal tumor (6 cm × 4.5 cm × 4.5 cm) invading the lower pole of the kidney and upper ureter. The final pathological diagnosis was organ-associated PMP with ossification. After 6-mo follow-up, no recurrence or metastasis was found. CONCLUSION: This case of PMP was unusual for its mimicking renal pelvic carcinoma in imaging examinations, making biopsy necessary.

[Clinical characterization of testicular yolk sac tumor in children and adults].

OBJECTIVE: To compare the clinical characteristics of simple testicular yolk sac tumor (YST) in children with those in adults so as to improve the diagnosis and treatment of the malignance. METHODS: This study included 75 cases of simple testicular YST pathologically confirmed between May 2008 and July 2018, which were divided into groups A (aged <18 years, n = 64) and B (aged ≥18 years, n = 11). We analyzed the clinical data on all the cases and compared the clinical manifestations, laboratory results, pathological findings, clinical stages, treatment methods and prognostic outcomes between the two groups of patients. RESULTS: The patients of group A ranged in age from 6 months to 5 years (ï¼»1.38 ± 0.89ï¼½ yr), with the tumor diameter of 0.9－6.0 (2.48 ± 1.12) cm, while those of group B from 25 to 49 years (median 34 years), with the tumor diameter of 3.5－6.3 (5.16 ± 1.32) cm, most presenting with a painless scrotal mass, 4 (6.2%) in group A and 5 (45.5%) in group B with testis pain. There were statistically significant differences between the two groups in the tumor diameter and initial manifestations (P < 0.05). All the patients were treated by radical high-level spermatectomy and orchiectomy and, in addition, 1 in group A and 3 in group B by retroperitoneal lymph node dissection (RPLND), 24 in the former and 5 in the latter group followed by chemotherapy. Elevated levels of serum alpha-fetoprotein (AFP) were observed in all the cases. Sixty-five of the patients were followed up for 10－78 (52.00 ± 23.78) months, during which 2 cases of simple metastasis, 3 cases of simple relapse, 3 cases of relapse with metastasis and 5 cases of death were found in group A, and 5 cases of simple metastasis, 1 case of simple relapse, 1 case of relapse with metastasis and 4 cases of death in group B. CONCLUSIONS: There are significant differences in the clinical manifestation, biological behavior, treatment and prognosis of testicular YST between children and adults. In children, most of the testicular YST cases are at clinical stage I and preferably treated by radical high-level spermatectomy and orchiectomy with favorable prognosis. In adults, however, the tumor is highly malignant, with high incidences of recurrence and metastasis and poor prognosis, for the treatment of which the first choice is radical high-level spermatectomy and orchiectomy combined with RPLND and chemotherapy.