Transcription Factor FOSL1 Promotes Angiogenesis of Colon Carcinoma by Regulating the VEGF Pathway Through Activating TIMP1.

Angiogenesis is the critical media for tumor growth and migration. Tissue Inhibitor Matrix Metalloproteinase-1 (TIMP1) acts as an oncogene in colon carcinoma (CC), but the biological effects of TIMP1 on angiogenesis remain an open issue. This study sought to explore the exact function and mechanism of TIMP1 in the angiogenesis of CC. Bioinformatics methods were utilized to analyze the expression of TIMP1 and its upstream transcription factor FOS-like antigen 1 (FOSL1) in the tumor tissue of CC. Meanwhile, in CC cell lines, real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were utilized to verify the expression of TIMP1 and FOSL1. Cell counting kit-8 and tube formation assays were utilized to analyze the proliferation and angiogenesis abilities of human umbilical vein endothelial cells (HUVECs). Western blot was used to detect the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out to explore the specific interaction between FOSL1 and TIMP1. The present study discovered that TIMP1 and FOSL1 were evidently up-regulated in CC tissue and cells. Meanwhile, TIMP1 was found to participate in regulating the signaling pathway of vascular endothelial growth factor (VEGF). Silenced TIMP1 conspicuously suppressed the proliferation and angiogenesis of HUVECs and reduced the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Moreover, FOSL1 could promote TIMP1 transcription by binding with its promoter and the inhibition of TIMP1 expression obviously reversed the promotion effects of FOSL1 overexpression on the proliferation and angiogenesis of HUVECs. FOSL1 activated VEGF pathway by up-regulating TIMP1 expression, thereby advancing CC angiogenesis. We provided theoretical basis that the FOSL1/TIMP1/VEGF pathway might be a novel option for anti-angiogenesis therapy of CC.

Neoadjuvant Radiotherapy Versus Surgery Alone for Stage II/III Mid-low Rectal Cancer With or Without High-risk Factors: A Prospective Multicenter Stratified Randomized Trial.

OBJECTIVE: The aim of this study was to compare stage II/III rectal cancers with or without high-risk factors, and evaluate the effect of neoadjuvant radiotherapy (NRT) in these 2 cohorts. BACKGROUND: NRT is often used in stage II/III rectal cancers to improve local control, while not affecting overall survival. However, good-quality surgery without NRT may also achieve good local control in selected patients. METHODS: According to risk-stratification criteria and clinical staging, consecutive eligible participants of stage II/III rectal cancer were preoperatively classified into patients with (high-risk) or without (low-risk) high-risk factors. Both groups were respectively randomized to receive either short-course radiotherapy (SCRT) + total mesorectal excision (TME) or TME alone, forming the following 4 groups: high-risk patients with (HiR) or without (HiS) radiation, and low-risk patients with (LoR) or without (LoS) radiation. The primary endpoint was local recurrence. The secondary endpoints included overall survival, disease-free survival, distant recurrence, quality of surgery, and safety (NCT01437514). RESULTS: In total, 401 patients were analyzed. With a median 54 months' follow-up, low-risk patients obtained better 3-year cumulative incidence of local recurrence (2.2% vs 11.0%, P = 0.006), overall survival rate (86.9%vs 76.5%, P = 0.002), disease-free survival rate (87.0% vs 67.9%, P < 0.001), and cumulative incidence of distant recurrence (12.5% vs 29.4%, P < 0.001) than high-risk patients. With regard to 3-year cumulative incidence of local recurrence, no differences were observed between the LoR and LoS groups (1.2% vs 3.0%, P = 0.983) or the HiR and HiS groups (12.9% vs 8.9%, P = 0.483). CONCLUSIONS AND RELEVANCE: Stratification of stage II/III rectal cancers according to risk factors to more precise subclassifications may result in noteworthy differences in survivals and local pelvic control. An extremely low cumulative incidence of local recurrence and survivals in low-risk patients can be achieved with upfront good quality of surgery alone. This trial, owing to the insufficient power, could not prove the noninferiority of surgery alone, but suggest a discriminative use of NRT according to clinical risk stratification in stage II/III rectal cancer.

Association between RAD51 gene polymorphism (-135G/C) and susceptibility of myelodysplastic syndrome and acute leukemia: evidence based on a meta-analysis.

Study results on the association between RAD51 gene -135G/C polymorphism and risk of myelodysplastic syndrome (MDS) or acute leukemia are inconsistent. A meta-analysis was conducted to identify the association. A systematic search was performed in PubMed, Embase, CNKI, VIP, Wanfang databases to collect all relevant studies until January 2013. Meta-analysis was carried out using fixed/random model by Review Manager 5.1 and STATA10.0. A total of 10 eligible studies with 2,656 patients and 3,725 controls were included in meta-analysis. Significant association was detected between -135G/C polymorphism and increased MDS risk (CC + GC vs. GG: OR = 1.46, 95% CI = 1.11-1.92; CC vs. GC + GG: OR = 2.45, 95% CI = 1.23-4.89), while no association was observed for acute leukemia. Subgroup analysis by subtypes of acute leukemia and ethnicity showed no significant results either. Our meta-analysis indicated that the -135G/C polymorphism might be associated with increased susceptibility of MDS. However, lack of evidence supported association of this polymorphism with acute leukemia. Additional well-designed studies with larger samples are required to verify our results.

NBS1 Glu185Gln polymorphism and cancer risk: update on current evidence.

A number of studies have investigated the association between NBS1 Glu185Gln (rs1805794, E185Q) polymorphism and cancer risk, but the results remained controversial. Previous meta-analysis found a borderline significant impact of this polymorphism on cancer risk; however, the result might be relatively unreliable due to absence of numerous newly published studies. Thus, we conducted an updated meta-analysis. A systematic search was performed in PubMed and Embase databases until April 9, 2013. The odds ratios were pooled by the fixed-effects/random-effects model in STATA 12.0 software. As a result, a total of 48 case-control studies with 17,159 cases and 22,002 controls were included. No significant association was detected between the Glu185Gln polymorphism and overall cancer risk. As to subgroup analysis by cancer site, the results showed that this polymorphism could increase the risk for leukemia and nasopharyngeal cancer. Notably, the Glu185Gln polymorphism was found to be related to increased risk for urinary system cancer, but decreased risk for digestive system cancer. No significant associations were obtained for other subgroup analyses such as ethnicity, sample size and smoking status. In conclusion, current evidence did not suggest that the NBS1 Glu185Gln polymorphism was associated with overall cancer risk, but this polymorphism might contribute to the risk for some specific cancer sites due to potential different mechanisms. More well-designed studies are imperative to identify the exact function of this polymorphism in carcinogenesis.

Better functional outcome provided by short-armed sigmoid colon-rectal side-to-end anastomosis after laparoscopic low anterior resection: a match-paired retrospective study from China.

PURPOSE: Side-to-end anastomosis using the descending colon has been proved to be as effective as J pouch in alleviating low anterior resection syndrome. However, using the sigmoid colon, which is less compliant for reconstruction after rectal cancer surgery, is common in China due to less prevalence of diverticulosis. The effectiveness of using the sigmoid colon for a side-to-end colorectal anastomosis in improving bowel dysfunction after laparoscopic low anterior resection of rectal cancer has not been investigated. This study was designed to compare the functional and surgical outcomes between the two anastomoses. METHODS: From October 2007 to December 2008, 16 rectal cancer patients underwent laparoscopic low anterior resection with short-armed (length of side limb 2-4 cm) side-to-end sigmoidorectal anastomosis at our department. The bowel functional results of these patients at 6 months and 1 year postoperatively were recorded and compared with that of another 1:2 matched 30 patients undergoing straight anastomosis. RESULTS: Bowel movement frequency in the side-to-end group was obviously less than that in the straight group 6 months postoperatively. Patients in the side-to-end group also had an improved incontinence score, a better ability to defer defecation, and less repeated evacuation. No differences were found between two groups 1 year after surgery. CONCLUSION: The study shows that the short-armed side-to-end colorectal anastomosis using the sigmoid colon can also improve the short-term bowel function in patients undergoing laparoscopic low anterior resection.

Reference Data of Phase Angle Using Bioelectrical Impedance Analysis in Overweight and Obese Chinese.

Introduction: Phase angle (PhA) is a ratio of reactance and resistance {arctangent (reactance (Xc)/resistance (R)) × (180°/π)}, which can be obtained by bioelectrical impedance analysis (BIA). PhA indicates cellular health and integrity, and it is also considered as a prognostic tool in medical disorders and an indicator of nutritional status (especially of muscle quality) in patients with obesity. However, PhA has limited usefulness in clinical practice because of a lackness of reference values for Chinese overweight and obese populations. The main aim of this study was to show PhA reference data in different age and BMI groups by sex. In addition, we also study the association of age, sex, and BMI on PhA. Methods: A total of 1729 overweight and obese participants were included in this study. PhA and body composition were measured using segmental multifrequency BIA. Differences in mean values for variables were tested by one-way analysis of variance. Multiple regression analysis was used to assess the associations of PhA with age, sex and BMI. Results: Multiple regression analysis showed that age, sex and BMI were significant (P < 0.05) independent influence factors of PhA in Chinese overweight and obese adults when age and BMI were continues variables. The mean PhA value for all participants was 5.5°. Mean BMI, age, weight, height and 50kHz-PhA were significantly higher (P < 0.001) in male participants than female ones. In age groups and BMI groups, mean 50kHz-PhA was significantly higher (P < 0.005) in male participants than female ones. When age groups and BMI groups were categorical variables, multiple regression analysis showed that different age groups (46-55 years and ≥ 56 years) had a significantly lower (P < 0.005) PhA as compared with the baseline group (18-25 years) and different BMI groups (≥ 28 kg/m2) had a significantly higher (P < 0.05) PhA as compared with the baseline group (24-27.9 kg/m2). Conclusion: PhA differed according to age, sex and BMI. Reference data in this study can be taken into consideration when deriving the reference values for overweight and obese Chinese populations.

Artificial Intelligence-Aided Colonoscopy for Polyp Detection: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Background: This study aimed to compare artificial intelligence (AI)-aided colonoscopy with conventional colonoscopy for polyp detection. Methods: A systematic literature search was performed in PubMed and Ovid for randomized clinical trials (RCTs) comparing AI-aided colonoscopy with conventional colonoscopy for polyp detection. The last search was performed on July 22, 2020. The primary outcome was polyp detection rate (PDR) and adenoma detection rate (ADR). Results: Seven RCTs published between 2019 and 2020 with a total of 5427 individuals were included. When compared with conventional colonoscopy, AI-aided colonoscopy significantly improved PDR (P < .001, odds ratio [OR] = 1.95, 95% confidence interval [CI]: 1.75 to 2.19, I2 = 0%) and ADR (P < .001, OR = 1.72, 95% CI: 1.52 to 1.95, I2 = 33%). Besides, polyps in the AI-aided group were significantly smaller in size than those in conventional group (P = .004, weighted mean difference = -0.48, 95% CI: -0.81 to -0.15, I2 = 0%). In addition, AI-aided group detected significantly less proportion of advanced adenoma (P = .03, OR = 0.70, 95% CI: 0.50 to 0.97, I2 = 46%), pedicle polyps (P < .001, OR = 0.64, 95% CI: 0.49 to 0.83, I2 = 0%), and pedicle adenomas (P < .001, OR = 0.60, 95% CI: 0.44 to 0.80, I2 = 0%). Conclusion: AI-aided colonoscopy could significantly increase the PDR and ADR, especially for those with small size. Besides, the shape and pathology recognition of the AI technique should be further improved in the future.

Fatty Acid Metabolism-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Patients With Colorectal Cancer.

Abnormal metabolism, including abnormal fatty acid metabolism, is an emerging hallmark of cancer. The current study sought to investigate the potential prognostic value of fatty acid metabolism-related long noncoding RNAs (lncRNAs) in colorectal cancer (CRC). To this end, we obtained the gene expression data and clinical data of patients with CRC from The Cancer Genome Atlas (TCGA) database. Through gene set variation analysis (GSVA), we found that the fatty acid metabolism pathway was related to the clinical stage and prognosis of patients with CRC. After screening differentially expressed RNAs, we constructed a fatty acid metabolism-related competing endogenous RNA (ceRNA) network based on the miRTarBase, miRDB, TargetScan, and StarBase databases. Next, eight fatty acid metabolism-related lncRNAs included in the ceRNA network were identified to build a prognostic signature with Cox and least absolute shrinkage and selection operator (LASSO) regression analyses, and a nomogram was established based on the lncRNA signature and clinical variables. The signature and nomogram were further validated by Kaplan-Meier survival analysis, Cox regression analysis, calibration plots, receiver operating characteristic (ROC) curves, decision curve analysis (DCA). Besides, the TCGA internal and the quantitative real-time polymerase chain reaction (qRT-PCR) external cohorts were applied to successfully validate the robustness of the signature and nomogram. Finally, in vitro assays showed that knockdown of prognostic lncRNA TSPEAR-AS2 decreased the triglyceride (TG) content and the expressions of fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) in CRC cells, which indicated the important role of lncRNA TSPEAR-AS2 in modulating fatty acid metabolism of CRC. The result of Oil Red O staining showed that the lipid content in lncRNA TSPEAR-AS2 high expression group was higher than that in lncRNA TSPEAR-AS2 low expression group. Our study may provide helpful information for fatty acid metabolism targeting therapies in CRC.

Corrigendum: Fatty Acid Metabolism-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Patients With Colorectal Cancer.

[This corrects the article DOI: 10.3389/fonc.2021.704038.].

Prognostic Nomogram for Childhood Acute Lymphoblastic Leukemia: A Comprehensive Analysis of 673 Patients.

OBJECTIVE: Despite that the survival rate in childhood acute lymphoblastic leukemia (cALL) is excellent, subsets of high-risk patients with cALL still have high relapse rates, and the cure rate is well below that for which we should aim. The present study aims to construct a prognostic nomogram to better inform clinical practitioners and improve risk stratification for clinical trials. METHODS: The developed nomogram was based on the therapeutically applicable research to generate effective treatment (TARGET) database. With this database, we obtained 673 cALL patients with complete clinical information. We identified and integrated significant prognostic factors to build the nomogram model by univariate and multivariate Cox analysis. The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index (C-index), calibration curve, and area under the receiver operating characteristic (ROC) curve (AUC) of ROC analysis. Internal validations were assessed by the bootstrapping validation. RESULTS: In the multivariate analysis of the primary cohort, the independent factors for survival were ETV6 RUNX1 fusion status, karyotype, minimal residual disease (MRD) at day 29, and DNA index, which were all integrated into the nomogram. The calibration curve for the probability of survival showed good agreement between the prediction by the nomogram and the actual observation. The C-index of the nomogram for predicting survival was 0.754 (95% CI, 0.715-0.793), and the AUCs for 3-, 5-, and 7-year survival were 0.775, 0.776, and 0.772, respectively. CONCLUSION: We comprehensively evaluated the risk of clinical factors associated with prognosis and carried out risk stratification. The nomogram proposed in this study objectively and accurately predicted the prognosis of children with ALL.

Development and validation of a novel prognostic signature in gastric adenocarcinoma.

Competing endogenous RNA networks have attracted increasing attention in gastric adenocarcinoma (GA). The current study aimed to explore ceRNA-based prognostic biomarkers for GA. RNA expression profiles were downloaded from TCGA and GEO databases. A ceRNA network was constructed based on the most relevant modules in the weighted gene coexpression network analysis. Kaplan-Meier (KM) survival analysis revealed prognosis-related RNAs, which were subjected to the multivariate Cox regression analysis. The predictive accuracy and discriminative ability of the signature were determined by KM analyses, receiver operating characteristic curves and area under the curve values. Ultimately, we constructed a ceRNA network consisting of 55 lncRNAs, 17 miRNAs and 73 mRNAs. Survival analyses revealed 3 lncRNAs (LINC01106, FOXD2-AS1, and AC103702.2) and 3 mRNAs (CCDC34, ORC6, and SOX4) as crucial prognostic factors; these factors were then used to construct a survival specific ceRNA network. Patients with high risk scores exhibited significantly worse overall survival than patients with low risk scores, and the AUC for 5-year survival was 0.801. A total of 112 GA specimens and the GSE84437 dataset were used to successfully validate the robustness of our signature by qRT-PCR. In summary, we developed a prognostic signature for GA, that shows better accuracy than the traditional TNM pathological staging system.

Circular RNA SAMD4A controls adipogenesis in obesity through the miR-138-5p/EZH2 axis.

A growing body of evidence has suggested that circular RNAs (circRNAs) are crucial for the regulation of gene expression and their dysregulation is implicated in several diseases. However, the function of circRNAs in obesity remains largely unexplored. Methods: Global changes in the circRNA expression patterns were detected in adipose tissues derived from obese and lean individuals. In particular, circSAMD4A was identified as significantly differentially upregulated and was functionally analyzed, both in vitro and in vivo, using various approaches. Results: CircSAMD4A overexpression was correlated with a poor prognosis in obese patients. By contrast, circSAMD4A knockdown inhibited differentiation in isolated preadipocytes. In high-fat diet (HFD) -induced obese mice, circSAMD4A knockdown reversed the associated weight gain, reduced food intake, lower body fat, and increased energy expenditure. These mice also exhibited increased insulin sensitivity and glucose tolerance. Furthermore, in vitro experiments indicated that circSAMD4A affected differentiation by binding to miR-138-5p and regulating EZH2 expression. Conclusions: CircSAMD4A regulated preadipocyte differentiation by acting as a miR-138-5p sponge, and thus increasing EZH2 expression. These results suggested that circSAMD4A can serve as a potential target for obesity treatments and/or as a potential prognostic marker for obese patients following bariatric surgery.

The lncRNA RP11-142A22.4 promotes adipogenesis by sponging miR-587 to modulate Wnt5ß expression.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) play essential roles in the regulation of gene expression. However, the functional contributions of lncRNAs to adipogenesis remain largely unexplored. In this study, we investigated global changes in the expression patterns of lncRNAs in visceral adipose tissue and identified RP11-142A22.4 as a significantly upregulated lncRNA. In isolated preadipocytes, knockdown of RP11-142A22.4 inhibited differentiation and reduced C/EBP-α and PPAR-γ expression. Investigations of the underlying mechanisms revealed that RP11-142A22.4 contains a functional miR-587 binding site. Mutation of the binding sites for RP11-142A22.4 in miR-587 abolished the interaction, as indicated by a luciferase reporter assay. Furthermore, RP11-142A22.4 affected the expression of miR-587 and its target gene Wnt5ß. Overexpression of miR-587 blocked the inhibitory effect of RP11-142A22.4 on preadipocyte differentiation. Moreover, the downregulation of miR-587 restored preadipocyte differentiation upon inhibition by RP11-142A22.4 silencing. Our results suggest that RP11-142A22.4 can control adipocyte differentiation via the miR-587/Wnt5ß signaling pathway and serve as a potential target for obesity treatments.