Noninvasive predictive models based on lifestyle analysis and risk factors for early-onset colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.

FBXW7 expression is associated with prognosis and chemotherapeutic outcome in Chinese patients with gastric adenocarcinoma.

BACKGROUND: FBXW7, a component of the Skp-Cullin1-F-box, mediates target protein recognition. It is a tumor suppressor gene that plays a role in the regulation of cell cycle exit and reentry via c-Myc, c-Jun and Notch degradation. There are few studies, particularly involving a large patient cohort, that have evaluated FBXW7 during gastric cancer progression. METHODS: Our study aimed to evaluate the value of FBXW7 as a clinical marker in gastric adenocarcinoma (GC) patients including a subset treated with postoperative chemotherapy. Quantitative reverse transcription PCR (qRT-PCR) assay was used to measure FBXW7 transcript levels in tumors paired with normal gastric tissue in 24 gastric adenocarcinoma patients. Subsequently, 546 additional GC samples were evaluated from patients that underwent radical gastrectomy, including 118 early stage cases(Stage I) and 428 advanced stage cases (Stages II or III). Amongst the advanced stage patient cases evaluated, 347 received postoperative adjuvant chemotherapy. All 546 gastric adenocarcinoma cases were then evaluated by tissue microarray and immunohistochemistry (IHC) for FBXW7 expression. Clinicopathological features and diagnoses were confirmed by histopathologic evaluation and review of clinical data. Overall survival (OS) was then evaluated in the 546 gastric cancer patients. RESULTS: By immunohistologic evaluation, low expression of FBXW7 in primary gastric cancer significantly correlated with poor differentiation of tumor cells. Moreover, low FBXW7 expression was associated with worse survival as well as worse adjuvant chemotherapy response. CONCLUSION: Our findings suggest that FBXW7 may serve as an important predictor in chemotherapeutic responses.

MAOA suppresses the growth of gastric cancer by interacting with NDRG1 and regulating the Warburg effect through the PI3K/AKT/mTOR pathway.

OBJECTIVE: Previous studies have indicated that neurotransmitters play important roles in the occurrence and development of gastric cancer. MAOA is an important catecholamine neurotransmitter-degrading enzyme involved in the degradation of norepinephrine, epinephrine and serotonin. To find a potential therapeutic target for the treatment of gastric cancer, the biological functions of MAOA and the underlying mechanism in gastric cancer need to be explored. METHODS: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets, Kaplan‒Meier (KM) plotter were used to identify the differentially expressed genes, which mainly involved the degradation and synthesis enzymes of neurotransmitters in gastric cancer. We also investigated the expression pattern of MAOA in human and mouse tissues and cell lines by immunohistochemistry and Western blotting analysis. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and a Seahorse experiment were used to identify the molecular mechanism of cancer cell glycolysis. MAOA expression and patient survival were analysed in the Ren Ji cohort, and univariate and multivariate analyses were performed based on the clinicopathological characteristics of the above samples. RESULTS: MAOA expression was significantly downregulated in gastric cancer tissue and associated with poor patient prognosis. Moreover, the expression level of MAOA in gastric cancer tissue had a close negative correlation with the SUXmax value of PET-CT in patients. MAOA suppressed tumour growth and glycolysis and promoted cancer cell apoptosis. We also reported that MAOA can interact with NDRG1 and regulate glycolysis through suppression of the PI3K/Akt/mTOR pathway. MAOA expression may serve as an independent prognostic factor in gastric cancer patients. CONCLUSIONS: MAOA attenuated glycolysis and inhibited the progression of gastric cancer through the PI3K/Akt/mTOR pathway. Loss of function or downregulation of MAOA can facilitate gastric cancer progression. Overexpression of MAOA and inhibition of the PI3K/Akt/mTOR pathway may provide a potential method for gastric cancer treatment in clinical therapeutic regimens.

Recent advances in multidisciplinary therapy for adenocarcinoma of the esophagus and esophagogastric junction.

Esophageal adenocarcinoma (EAC) and adenocarcinoma of the esophagogastric junction (EGJA) have long been associated with poor prognosis. With changes in the spectrum of the disease caused by economic development and demographic changes, the incidence of EAC and EGJA continues to increase, making them worthy of more attention from clinicians. For a long time, surgery has been the mainstay treatment for EAC and EGJA. With advanced techniques, endoscopic therapy, radiotherapy, chemotherapy, and other treatment methods have been developed, providing additional treatment options for patients with EAC and EGJA. In recent decades, the emergence of multidisciplinary therapy (MDT) has enabled the comprehensive treatment of tumors and made the treatment more flexible and diversified, which is conducive to achieving standardized and individualized treatment of EAC and EGJA to obtain a better prognosis. This review discusses recent advances in EAC and EGJA treatment in the surgical-centered MDT mode in recent years.

Prognostic and pathological impact of tumor budding in gastric cancer: A systematic review and meta-analysis.

BACKGROUND: Tumor budding, is a promising prognostic hallmark in many cancers, and can help us better assess the degree of malignancy in gastric cancer (GC) and in colorectal cancer. In the past few years, several articles on the relationship between tumor budding and GC have been published, but different results have been observed. As the relationship between tumor budding and GC remains controversial, we integrated the data from 7 eligible studies to conduct a systematic review and meta-analysis. AIM: To systematically evaluate the prognostic and pathological impact of tumor budding in GC. METHODS: Literature searches were conducted in the PubMed, Cochrane Library, EMBASE and Web of Science databases, and 7 cohort studies involving 2178 patients met our criteria and included in the analysis. The patients were divided into those with high-grade tumor budding and those with low-grade tumor budding, and the cut-off values for tumor budding varied across the included studies. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the impact of tumor budding on overall survival (OS) in GC patients. The odds ratios (ORs) with 95%CIs were used to determine the correlation between tumor budding and pathological parameters (tumor stage, tumor differentiation, lymphovascular invasion, lymph node metastasis) of GC. RESULTS: Seven studies involving 2178 patients were included in the meta-analysis. The combined ORs suggested that high-grade tumor budding was significantly associated with tumor stage (OR = 6.63, 95%CI: 4.01-10.98, P < 0.01), tumor differentiation (OR = 3.74, 95%CI: 2.68-5.22, P < 0.01), lymphovascular invasion (OR = 7.85, 95%CI: 5.04-12.21, P < 0.01), and lymph node metastasis (OR = 5.75, 95%CI: 3.20-10.32, P < 0.01). Moreover, high-grade tumor budding predicted a poor 5-year OS (HR = 1.79, 95%CI: 1.53-2.05, P < 0.01) in patients with GC and an adverse 5-year OS (HR = 1.93, 95%CI: 1.45-2.42, P < 0.01) in patients with intestinal-type GC. CONCLUSION: High-grade tumor budding suggested a poor prognosis in patients with GC or intestinal-type GC.

Current status of surgical treatment of gastric cancer in the era of minimally invasive surgery in China: Opportunity and challenge.

Gastric cancer is one of the most common cancers in China. In the past decade, with the developments in surgical instruments and technologies, minimally invasive surgery has rapidly become an accepted treatment for gastric cancer in China. Many Chinese surgeons and researchers have contributed to the rapid evolution of minimally invasive surgery for gastric cancer. Their efforts have transformed into unique laparoscopic technique, workshops, academic communications, education and international communications in China. Meanwhile, many retrospective comparative trials and randomized controlled trials have revealed the advantages in minimally invasive surgery for gastric cancer. However, multicenter randomized controlled trials are still needed to delineate significantly quantifiable differences between laparoscopic and open gastrectomy. With more and more experience has accumulated, laparoscopic gastrectomy has been performed on older and overweight patients. Moreover, advanced minimally invasive techniques, such as modified laparoscopic spleen-preserving splenic hilum lymphadenectomy, various laparoscopic gastric reconstruction methods and robotic gastrectomy have been developed. It seems that China owns the potential to keep up with her neighbor, Japan and Korea, to become one of leading countries utilizing minimally invasive surgery for gastric cancer.

TEM7 (PLXDC1), a key prognostic predictor for resectable gastric cancer, promotes cancer cell migration and invasion.

Tumor endothelial marker 7 (TEM7) is a new candidate of molecular target for antiangiogenic therapy. This study aims to evaluate its expression in gastric cancer (GC) and to explore the correlation between its expression and the clinical outcome of patients. Expression of TEM7 was analyzed in both tumor tissues and cell lines of GC by real-time quantitative RT-PCR (qRT-PCR) and Western blot. RNA interference (RNAi) approaches were used to investigate the biological functions of TEM7. The effects of TEM7 on cell migration and invasion were evaluated by Transwell assays. In vitro experiments revealed that TEM7 was significantly overexpressed in GC cell lines (N87, AGS and SGC-7901) by 2-fold to 4-fold, and knockdown of TEM7 could significantly inhibit cancer cell migration and invasion. For GC patients, TEM7 gene expression was elevated in tumors in most cases (25/31), and its expression was closely correlated with tumor differentiation, depth of cancer invasion, lymphatic metastasis and TNM stage. The overall survival of TEM7 (-) group was significantly higher than that of TEM7 (+) group (P = 0.048) and TEM7 (++) group (P = 0.003). TEM7 is highly expressed in GC and is likely correlated with tumor invasion and migration, and thus its expression is closely related to the clinical outcome of patients.

HOTAIR Long Noncoding RNA Promotes Gastric Cancer Metastasis through Suppression of Poly r(C)-Binding Protein (PCBP) 1.

The objective of this study was to evaluate the role of HOTAIR long noncoding RNA in gastric cancer metastasis. We analyzed HOTAIR expression levels by real-time reverse transcription PCR and Northern blot analysis in 100 gastric tissues (50 gastric cancer tissues and 50 adjacent normal mucosa), and in four gastric cancer cell lines. Transient RNAi-mediated knockdown and pcDNA-mediated overexpression of HOTAIR were performed. Stable shRNA-mediated knockdown and lentiviral-mediated overexpression of HOTAIR were to study the role of HOTAIR on in vivo tumorigenicity and metastatic burden in the context of xenograft assays. Proteomic profiling was performed to decipher differential protein expression in cells with different HOTAIR expression levels. One of the differentially regulated proteins, Poly r(C)-binding protein (PCBP) 1, was subsequently validated and its function evaluated through xenograft assays. Expression of HOTAIR was significantly higher in cancerous tissues than in adjacent normal mucosa. HOTAIR expression levels dictated in vitro and in vivo tumorigenicity and metastatic potential in these cells. PCBP1 and HOTAIR have an inverse relationship, both at expression level and in function. A direct interaction between the two was confirmed through RNA immunoprecipitation coupled with quantitative real-time PCR. PCBP1 was confirmed to be an inhibitor of gastric cancer pathogenesis and as functionally opposite to HOTAIR long noncoding RNA. In conclusion, HOTAIR expression may serve as a potentially important disease biomarker for the identification of high-risk gastric cancer patients. Moreover, our findings provide mechanistic evidence for HOTAIR overexpression and PCBP1 downregulation and the ensuing malignant phenotype in both cultured and xenograft gastric cancer cells.

miR-375 inhibits the proliferation of gastric cancer cells by repressing ERBB2 expression.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of targeted genes in a post-transcriptional manner. Increasing evidence indicates that miRNAs play important roles in cancer pathogenesis, including apoptosis, proliferation and differentiation, as oncogenes or tumor suppressors. Previously, miR-375 was shown to be involved in human gastric cancer, however, the mechanism remains poorly understood. In the present study, miR-375 was shown to be downregulated in gastric cancer tissues, particularly human epidermal growth factor receptor 2 (ERBB2)-positive gastric cancer tissues. Identified by dual luciferase assays and western blot analysis, ERBB2 was demonstrated to be a target gene of miR-375. In addition, miR-375 overexpression suppressed the proliferation of human gastric cancer cells in vitro and the suppression effect was restored by ERBB2 overexpression. Thus, the results of the present study indicate that miR-375 is associated with human gastric carcinogenesis by targeting ERBB2. Therefore, miR-375 may be used as a potential clinical classification marker and therapeutic target for human gastric cancer.

[Influence of silencing Notch1 on proliferation, migration and invasion of BGC-823 gastric cancer cells].

OBJECTIVE: To investigate the role of Notch1 in the proliferation, migration and invasion of gastric cancer cells. METHODS: Notch1 expression was detected by RT-PCR and Western blot in four gastric cancer cell lines(SGC-7901, BGC-823, MKN-45 and MKN-28). The RNAi segments targeting Notch1 were designed and transfected into cell lines with the highest level of Notch1. The transcription and translation level of Notch1 expression was detected by real-time PCR and Western blot. The proliferation of transfected cells were determined by CCK8 test. Meanwhile, the migration and invasive ability of transfected tumor cells were detected by Transwell test. RESULTS: Gastric cell line BGC-823 was selected with the highest expression of Notch1 at both mRNA level and protein level. The expression of Notch1 was significantly reduced after the transfection. The CCK8 test showed the growth rate was significantly reduced in RNAi group after two days(F=4.644, P=0.046). In migration test, the number of cells crossing through chambers in RNAi group(30.1±3.1) was significantly lower than that in the negative control group(44.5±3.2) and in the mock group(46.1±2.6)(P<0.05). In invasion test, the number of cells crossing through chambers in RNAi group(22.9±4.5) was also significantly lower than that in the negative control group (37.3±4.2) and in the mock group (37.8±3.7)(P<0.05). CONCLUSION: Down-regulation of Notch1 inhibits the proliferation and reduces the ability of migration and invasion in gastric cell line BGC-823, suggesting that Notch1 may play an important role in the gastric carcinogenesis and metastasis.

Clinical significance of human kallikrein 12 gene expression in gastric cancer.

AIM: To investigate whether the expression of kallikrein 12 (KLK12) is related to the development of gastric cancer (GC) and to determine the role of KLK12 in gastric cancer cells growth, invasion and migration. METHODS: Between September 2007 and March 2008, 133 patients with histologically confirmed GC were recruited for the study. Expression of KLK12 was detected in samples from GC patients by quantitative real-time reverse transcription polymerase chain reaction and immunohistochemistry. The relationship between KLK12 protein expression and clinicopathological features of GC was analyzed. The difference in 5-year survival rates between the high KLK12 protein expression group and the low KLK12 expression group was compared. Additionally, the expression of KLK12 was examined in various human GC cell lines, including MKN-28, SGC-7901 and MKN-45. Small interfering RNA (siRNA) was used to inhibit KLK12 expression in MKN-45 cells. Cell clones stably transfected with KLK12 siRNA were tested for KLK12 expression by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. Furthermore, a series of functional assays were performed in this study to assess the biological features of transfected cells. Cell proliferation was assessed using the methylthiazolyltetrazoliumassay. Finally, cell migration and invasion were assessed using transwell chamber assays. RESULTS: Of the 133 GC patients included in the study, 126 (94.7%) showed a higher expression level of KLK12 mRNA when compared to noncancerous tissue specimens. Expression of KLK12 mRNA was significantly higher in GC tissues than in normal tissue (P < 0.001). KLK12 protein expression was detected in 96 of 133 (72.2%) GC samples with moderate or strong staining primarily in the cytoplasm. In contrast, negative immunostaining for KLK12 protein was observed in the corresponding normal gastric mucosal tissue. Overexpression of KLK12 protein was significantly associated with lymph node metastasis (P = 0.001), histological type (P < 0.001) and tumor-node-metastasis stage (P = 0.005), while no significant correlation was observed between expression of KLK12 protein and sex, age, depth of invasion, tumor size or lymphatic invasion. Furthermore, patients with high KLK12 expression had a significantly poorer 5-year survival rate than those with low KLK12 expression (P = 0.002). Expression of KLK12 mRNA was significantly higher in MKN-45 GC cells compared to normal mucosal cells or two other GC cell lines (P < 0.01). Expression of KLK12 in MKN-45 cells was downregulated after transfection with siRNA. Knockdown of KLK12 markedly decreased the proliferation of MKN-45 cells when compared with parent or mock-transfected cells (P = 0.001), especially from the 3rd to the 5th day of the assay. In migration assays, fewer KLK12 siRNA cells migrated through the chambers (22.00 ± 1.81) when compared to the parent (46.47 ± 2.42) or mock-transfected cells (45.40 ± 1.99); these differences were statistically significant (P < 0.001). However, in the invasion assay, the number of KLK12 siRNA cells that invaded the chambers was 18.40 ± 1.12, closely similar to both the parent (18.67 ± 0.98) and mock-transfected cells (18.53 ± 0.92). There was no significantly difference between the three groups in the invasion assay (P = 0.054). CONCLUSION: The KLK12 gene is markedly overexpressed in GC tissue, and its expression status may be a powerful prognostic indicator for patients with GC. KLK12 might serve as a novel diagnosis and prognosis biomarker in GC.