Influence of early colorectal cancer component on the positive margins after endoscopic resection: a retrospective study.

BACKGROUND: Endoscopic treatment methods for early colorectal cancer (ECRC) mainly depend on the size and morphology. It is unclear whether different endoscopic resection methods could achieve curative resection for ECRC confined in the mucosa. The study was designed to compare the rate of positive vertical margin (VM) of ECRC with advanced adenomas (AAs) including adenoma > 1 cm, villous adenoma, high-grade intraepithelial neoplasia/dysplasia stratified by different endoscopic resection methods. METHODS: Rate of positive VM for 489 ECRCs including Intramucosal (pTis) and superficial submucosal invasion (pT1) carcinomas were compared with those of 753 AAs stratified by different endoscopic resection methods using Chi-squared test. Multivariate logistic model was performed to investigate the risk factors of positive VM for different endoscopic resection methods. RESULTS: The pTis ECRC exhibited a similar rate of positive VM as that of AAs for en bloc hot snare polypectomy (HSP, 0% Vs. 0.85%, P = 0.617), endoscopic mucosal resection (EMR, 0.81% vs. 0.25%, P = 0.375) and endoscopic submucosal dissection (ESD, 1.82% Vs. 1.02%, P = 0.659). The pTis carcinoma was not found to be a risk factor for positive VM by en bloc EMR (P = 0.349) or ESD (P = 0.368). The en bloc resection achieved for pT1a carcinomas exhibited similar to positive VM achieved through ESD (2.06% Vs. 1.02%, P = 1.000) for AAs. Nonetheless, EMR resulted in higher risk of positive VM (5.41% Vs. 0.25%, P < 0.001) for pT1a carcinomas as compared to AAs. The pT1a invasion was identified as a risk factor for positive VM in polyps with en bloc EMR (odds ratio = 23.90, P = 0.005) but not ESD (OR = 2.96, P = 0.396). CONCLUSION: Collectively, the pTis carcinoma was not found to be a risk factor for positive VM resected by en bloc HSP, EMR or ESD. Additionally, ESD may be preferred over EMR for pT1a carcinomas with lower rate of positive VM.

Long- and short-term outcomes of early gastric cancer after endoscopic resection: a retrospective study from China.

Background and study aims The aim of the study was to evaluate short- and long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in China because no study has yet been conducted to confirm its effectiveness in EGC in China. Patients and methods A total of 570 EGC samples from 537 patients were collected for evaluation of en bloc, complete, and curative resection using ESD. Data from 302 patients with at least 3 years of active follow-up were collected for analysis of recurrence of EGC and occurrence of metachronous GC (MGC). Short- and long-outcomes of mixed-type and pure differentiated EGC were also compared. Results En bloc resection rates of 96.0 %, 98.7 %, and 95.2 %, complete resection rates of 91.2 %, 96.6 % and 90.8 %, and curative resection rates of 83.0 %, 96.2 % and 88.2 % were achieved in all EGCs included in the study, those with absolute indication, and those with expanded indication, respectively. As a long-term outcome, recurrence was observed in 1.3 % of patients, 3-year and 5-year recurrence rates being 0.7 % and 1.2 %, respectively. Thirteen patients (4.3 %) exhibited MGCs during follow-up, all of which were resected in a second ESD. Conclusions The effectiveness of ESD for EGC in China was confirmed, with satisfactory short- and long-term outcomes. With scheduled follow-up, the outcomes for mixed-type EGC can be similar to those for pure differentiated EGC after complete resection without development of lymphovascular invasion.

Patterns of Lymph Node Metastasis in Patients With T1/T2 Gastroduodenal Neuroendocrine Neoplasms: Implications for Endoscopic Treatment.

Guidelines have differed in their opinion regarding the indications for endoscopic resection of gastric-neuroendocrine neoplasms (g-NENs) and duodenal-NENs (d-NENs). We examined the association between size and lymph node metastasis (LNM) to identify candidates most suitable for endoscopic resection. We identified 706 patients with T1/T2 g-NENs and 621 patients with T1/T2 d-NENs from the SEER database. The prevalence of LNM and risk factors associated with LNM were analyzed. LNM was present in 8.1% of patients with gastroduodenal neuroendocrine tumors (NETs) and 31.6% of patients with neuroendocrine carcinomas (NECs). Multivariate logistic regression indicated that tumor size >10mm, greater invasion depth, and poor differentiation were independently associated with LNM. In addition, the percentage of g-NETs invading submucosa with LNM increased with tumor size (≤10 mm,3.9%;11-20 mm,8.6%;>20 mm,16.1%). However, in contrast to the low LNM risk in patients with small g-NETs (≤10 mm), we found that LNM rate exceeded 5% even for patients with small submucosal-infiltrating d-NETs. Among patients with nodal-negative g-NETs, the cause specific survival (CSS) was similar for those who received surgical resection and endoscopic resection. Among patients with d-NETs, the CSS was better for those who received endoscopic resection. In conclusion, patients with d-NETs had a higher probability of LNM than those with g-NETs. Endoscopic resection can be utilized for curative treatment of submucosa-infiltrating g-NETs and intramucosal d-NETs when the size is 10 mm or less. These results reinforce the need to search for LNM in lesions that are larger than 10 mm.

The role of early video capsule endoscopy in the diagnosis and prognosis of obscure gastrointestinal bleeding: A multi-center propensity score matching study.

BACKGROUND AND AIM: Video capsule endoscopy (VCE) is a first-line procedure for the diagnosis of obscure gastrointestinal bleeding (OGIB). The opinions on the timing for such diagnostic evaluation remain unclear. We aimed to explore the role of early VCE in OGIB patients. METHODS: A total of 997 patients that underwent VCE at Renji Hospital and Nagoya University from May 15, 2002, to December 28, 2016, were included in this study. We matched patients that underwent early VCE within 14 days of bleeding (early group, n = 678) to patients that did not (late group, n = 319) via 1:1 propensity score matching (PSM). We then compared VCE diagnostic rates and the prevalence of post-VCE rebleeding in patients with initial negative VCE findings within 1 year between these groups before and after PSM. RESULTS: Following PSM, early VCE was associated with a significantly higher rate of OGIB diagnosis (56.4% vs 45.5%, P = 0.001) and with a significantly lower incidence of rebleeding within 1 year following treatment (24.7% vs 36.7%, P = 0.041). In univariate and multivariate analyses, VCE timing (odds ratio 0.648; 95% confidence interval 0.496-0.847, P = 0.001 and odds ratio 0.666; 95% confidence interval 0.496-0.894, P = 0.007, respectively) was found to be linked with a higher rate of positive findings. CONCLUSION: Early VCE can improve the reliability of OGIB diagnosis while also reducing rates of post-VCE rebleeding. This suggests that timely and accurate diagnosis can help to improve OGIB patient treatment and prognosis.

Qualitative Transcriptional Signature for the Pathological Diagnosis of Pancreatic Cancer.

It is currently difficult for pathologists to diagnose pancreatic cancer (PC) using biopsy specimens because samples may have been from an incorrect site or contain an insufficient amount of tissue. Thus, there is a need to develop a platform-independent molecular classifier that accurately distinguishes benign pancreatic lesions from PC. Here, we developed a robust qualitative messenger RNA signature based on within-sample relative expression orderings (REOs) of genes to discriminate both PC tissues and cancer-adjacent normal tissues from non-PC pancreatitis and healthy pancreatic tissues. A signature comprising 12 gene pairs and 17 genes was built in the training datasets and validated in microarray and RNA-sequencing datasets from biopsy samples and surgically resected samples. Analysis of 1,007 PC tissues and 257 non-tumor samples from nine databases indicated that the geometric mean of sensitivity and specificity was 96.7%, and the area under receiver operating characteristic curve was 0.978 (95% confidence interval, 0.947-0.994). For 20 specimens obtained from endoscopic biopsy, the signature had a diagnostic accuracy of 100%. The REO-based signature described here can aid in the molecular diagnosis of PC and may facilitate objective differentiation between benign and malignant pancreatic lesions.

Personalized four-category staging for predicting prognosis in patients with small bowel Adenocarcinoma: an international development and validation study.

BACKGROUND: Log odds of positive lymph nodes (LODDS) classification showed superiority over 8th edition N staging in predicting survival of small bowel adenocarcinoma (SBA) patients. The aim of this study was to develop and validate the Tumor, LODDS, and Metastasis (TLM) staging of SBA. METHODS: Totally 1789 SBA patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1988-2010, 437 patients from SEER database between 2011-2013 and 166 patients from multicenters were categorized into development, validation and test cohort, respectively. The TLM staging was developed in the development cohort using Ensemble Algorithm for Clustering Cancer Data (EACCD) method. C-index was used to assess the performance of the TLM staging in predicting cancer-specific survival (CSS) and was compared with the traditional 8th edition TNM staging. FINDINGS: Four-category TLM staging designed for the development cohort showed higher discriminatory power than TNM staging in predicting CSS in the development cohort (0.682 vs. 0.650, P < 0.001), validation cohort (0.682 vs. 0.654, P = 0.022), and test cohort (0.659 vs. 0.611, P = 0.023), respectively. TLM staging continued to show its higher predictive efficacy than the 8th TNM in TNM stage II/III patients or in patients with lymph node yield less than 8. INTERPRETATION: TLM staging showed a better prognostic performance than the 8th TNM staging especially TNM stage II/III or patients with lymph node yield less than 8 and therefore, could serve to complement the TNM staging in patients with SBA. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Comparison of malignancy-prediction efficiency between contrast and non-contract CT-based radiomics features in gastrointestinal stromal tumors: A multicenter study.

This work seeks the development and validation of radiomics signatures from nonenhanced computed tomography (CT, NE-RS) to preoperatively predict the malignancy degree of gastrointestinal stromal tumors (GISTs) and the comparison of these signatures with those from contrast-enhanced CT. A dataset for 370 GIST patients was collected from four centers. This dataset was divided into cohorts for training, as well as internal and external validation. The minimum-redundancy maximum-relevance algorithm and the least absolute shrinkage and selection operator (LASSO) algorithm were used to filter unstable features. (a) NE-RS and radiomics signature from contrast-enhanced CT (CE-RS) were built and compared for the prediction of malignancy potential of GIST based on the area under the receiver operating characteristic curve (AUC). (b) The radiomics model was also developed with both the tumor size and NE-RS. The AUC values were comparable between NE-RS and CE-RS in the training (.965 vs .936; P = .251), internal validation (.967 vs .960; P = .801), and external validation (.941 vs .899; P = .173) cohorts in diagnosis of high malignancy potential of GISTs. We next focused on the NE-RS. With 0.185 selected as the cutoff of NE-RS for diagnosis of the malignancy potential of GISTs, accuracy, sensitivity, and specificity for diagnosis high-malignancy potential GIST was 90.0%, 88.2%, and 92.3%, respectively, in the training cohort. For the internal validation set, the corresponding metrics are 89.1%, 94.9%, and 80.0%, respectively. The corresponding metrics for the external cohort are 84.6%, 76.1%, and 91.0%, respectively. Compared with only NE-RS, the radiomics model increased the sensitivity in the diagnosis of GIST with high-malignancy potential by 5.9% (P = .025), 2.5% (P = .317), 10.5% (P = .008) for the training set, internal validation set, and external validation set, respectively. The NE-RS had comparable prediction efficiency in the diagnosis of high-risk GISTs to CE-RS. The NE-RS and radiomics model both had excellent accuracy in predicting malignancy potential of GISTs.

Prognosis of colorectal cancer patients is associated with the novel log odds of positive lymph nodes scheme: derivation and external validation.

Background and aim: To construct proper and externally validate cut-off points for log odds of positive lymph nodes scheme (LODDS) staging scheme in colorectal cancer (CRC). Patients and methods: The X-tile approach was used to find the cut-off points for the novel LODDS staging scheme in 240,898 patients from the Surveillance, Epidemiology and End Results (SEER) database and externally validated in 1,878 from the international multicenter cohort. Kaplan-Meier plot and multivariate Cox proportional hazard models were performed to investigate the role of the novel LODDS classification. Results: The prognostic cut-off values were determined as -2.18, and -0.23 (P< 0.001). Patients had 5-year cancer-specific survival rates of 83.8%, 57.4% and 24.4% with increasing LODDS (P< 0.001) in the SEER database. Five-year overall survival rates were 77.2%, 55.0% and 26.7% with increasing LODDS (P< 0.001) in the external international multicenter cohort. Multivariate survival analysis identified both the LODDS classification, the patient's age, the T category, the M status, and the tumor grade as independent prognostic factors in both two independent databases. The analyses of the subgroup of patients stratified by tumor location (colon or rectum), number of retrieved lymph node (< 12 or ≥ 12), TNM stage III, lymph node-negative also confirmed the LODDS as independent prognostic factors (P< 0.001) in both two independent databases. Conclusions: The novel LODDS classification was an independent prognostic factor for patients with CRCs and should be calculated for additional risk group stratification with pN scheme.

Personalized CT-based radiomics nomogram preoperative predicting Ki-67 expression in gastrointestinal stromal tumors: a multicenter development and validation cohort.

BACKGROUND AND AIM: To develop and validate radiomic prediction models using contrast-enhanced computed tomography (CE-CT) to preoperatively predict Ki-67 expression in gastrointestinal stromal tumors (GISTs). METHOD: A total of 339 GIST patients from four centers were categorized into the training, internal validation, and external validation cohort. By filtering unstable features, minimum redundancy, maximum relevance, Least Absolute Shrinkage and Selection Operator (LASSO) algorithm, a radiomic signature was built to predict the malignant potential of GISTs. Individual nomograms of Ki-67 expression incorporating the radiomic signature or clinical factors were developed using the multivariate logistic model and evaluated regarding its calibration, discrimination, and clinical usefulness. RESULTS: The radiomic signature, consisting of 6 radiomic features had AUC of 0.787 [95% confidence interval (CI) 0.632-0.801], 0.765 (95% CI 0.683-0.847), and 0.754 (95% CI 0.666-0.842) in the prediction of high Ki-67 expression in the training, internal validation and external validation cohort, respectively. The radiomic nomogram including the radiomic signature and tumor size demonstrated significant calibration, and discrimination with AUC of 0.801 (95% CI 0.726-0.876), 0.828 (95% CI 0.681-0.974), and 0.784 (95% CI 0.701-0.868) in the training, internal validation and external validation cohort respectively. Based on the Decision curve analysis, the radiomics nomogram was found to be clinically significant and useful. CONCLUSIONS: The radiomic signature from CE-CT was significantly associated with Ki-67 expression in GISTs. A nomogram consisted of radiomic signature, and tumor size had maximum accuracy in the prediction of Ki-67 expression in GISTs. Results from our study provide vital insight to make important preoperative clinical decisions.

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation.

BACKGROUND: Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide. METHODS: We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN. RESULTS: The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide. CONCLUSION: Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.

Inverse Association of Age with Risk of Lymph Node Metastasis in Superficial Colorectal Cancer: A Large Population-Based Study.

BACKGROUND: Superficial colorectal cancer (SCRC) is defined as colorectal cancer (CRC) confined to the mucosa or submucosa. Endoscopic resection (ER) is widely used to resect differentiated SCRC from patients without lymph node metastasis (LNM). However, it is unclear whether ER is suitable for use with patients with differentiated early-onset SCRC because early-onset CRC is more aggressive. Therefore, we aimed to investigate the association between age of CRC onset and LNM. MATERIALS AND METHODS: We retrieved data for patients with surgically resected differentiated-type SCRCs from the Surveillance, Epidemiology, and End Results (SEER) database. Rate of LNM was compared among patients aged 18-39, 40-49, 50-59, 60-69, and ≥70 years. The association between age and LNM was further examined using multivariate logistic regression. RESULTS: We retrieved 34,506 records of differentiated SCRCs from the SEER database, including 667 patients aged 18-39 years, 2,385 aged 40-49, 8,075 aged 50-59 years, 9,577 aged 60-69 years, and 13,802 aged ≥70 years. Rates of LNM were 15.74%, 14.13%, 10.67%, 8.07%, and 6.76% for patients aged 18-39, 40-49, 50-59, 60-69, and ≥70 years, respectively. We found an inverse correlation between age at diagnosis and risk of LNM from the univariate analysis (p < .001). Compared with patients aged 18-39, the odds ratios with 95% confidence interval (CI) for patients aged 40-49, 50-59, 60-69, and ≥70 years were 0.90 (0.71-1.15, p = .376), 0.69 (0.56-0.87, p = .001), 0.54 (0.43-0.68, p < .001), and 0.47 (0.38-0.60, p < .001), respectively. CONCLUSION: In differentiated SCRCs, younger age at diagnosis was associated with higher risk of LNM. IMPLICATIONS FOR PRACTICE: Endoscopic resection (ER) is widely used to resect differentiated superficial colorectal cancer (SCRC) without lymph node metastasis (LNM). However, no study has ever investigated risk of LNM of early-onset SCRC compared with average onset SCRC to explore whether ER is suitable for early-onset SCRC. To the authors' knowledge, this population-based study is the first study to find inverse correlation between age at diagnosis and risk of LNM in differentiated SCRCs. This finding indicates that ER may not be suitable for young patients with differentiated SCRC. Because the 30-day operative mortality after surgery is higher but the risk of LNM is lower in older patients compared with younger patients, ER for differentiated SCRCs may be advantageous over surgery for older patients.

Feasibility of using narrow band imaging international colorectal endoscopic classification for diagnosing colorectal neoplasia in China: A multicenter pilot observational study.

OBJECTIVE: We aimed to investigate whether Chinese endoscopists without narrow-band imaging (NBI) experiences could achieve high accuracy in the real-time diagnosis of colorectal polyps using NBI International Colorectal Endoscopic (NICE) classification after web-based training. METHODS: Altogether 15 endoscopists from five centers with no NBI experiences followed a short, web-based training program on the NICE classification and took web-based test. Their performances were compared with 15 matched experienced endoscopists with no NBI experience who received no NBI training. These 15 trained endoscopists then made real-time diagnoses of colorectal neoplasia. A logistic regression was used to assess potential predictors of diagnostic performance. RESULTS: Compared with those who received no training, trained endoscopists achieved comparable overall accuracy (85.3% vs 83.1%, P = 0.408) and accuracy at a high-confidence level (87.0% vs 86.0%, P = 0.670), but had a higher confidence rate (86.1% vs 83.7%, P = 0.004) for the diagnosis of neoplasia. Real-time diagnostic accuracy, sensitivity and specificity were 94.3% (95% confidence interval [CI] 91.5%-96.2%), 96.2% (95% CI 93.4%-97.9%) and 85.3% (95% CI 74.8%-92.1%) at high-confidence level. The high-confidence level was the strongest predictor of real-time diagnostic accuracy (odds ratio 12.66, P < 0.001). CONCLUSIONS: Web-based training can improve the confidence level of endoscopists in accurately diagnosing colorectal polyps using the NICE classification. Chinese endoscopists can achieve high accuracy in diagnosing colorectal neoplasia at a high confidence level (ClinicalTrials ID: NCT02033980).

Low-dose and same day use of polyethylene glycol improves image of video capsule endoscopy: A multi-center randomized clinical trial.

BACKGROUND AND AIM: Clear visualization of the small bowel is a requirement for satisfactory video capsule endoscopy (VCE). The aim of this study was to identify the optimal dose and timing of polyethylene glycol (PEG) for small bowel preparation before VCE. METHODS: A total of 410 patients were enrolled in this prospective randomized trial. All patients fasted for 12 h and ingested 320 mg simethicone 30 min before swallowing the capsule. Patients were randomized into five groups: Group A (no PEG), Group B (1-L PEG, 12 h before VCE), Group C (2-L PEG, 12 h before VCE), Group D (1-L PEG, 4 h before VCE), and Group E (2-L PEG, 4 h before VCE). The primary endpoint was small bowel visualization quality (SBVQ), and the secondary endpoints were patient acceptability and diagnosis rate of VCE. RESULTS: Excellent SBVQ was achieved in 27 (32.5%) of Group A, 38 (46.3%) of Group B, 40 (48.2%) of Group C, 55 (66.3%) of Group D, and 43 (54.4%) of Group E. The percentage of excellent SBVQ in Group D was significantly more than in Group A (66.3% vs 32.5%, P < 0.001), and diagnostic rate in the distal segment was higher (28.9% vs 10.8%, P = 0.0035). Patient acceptance of 1-L PEG was better than of 2-L PEG (P < 0.005). CONCLUSION: Small bowel cleansing with 1-L PEG given 4 h before VCE was the optimal preparation for visualization of the bowel and patient acceptance (ClinicalTrials.gov, ID: NCT02486536).

Endoscopic management of patients with early gastric cancer before and after endoscopic resection: A review.

With the wide application of endoscopic resection for early gastric cancer (EGC) by not only Asian endoscopists but also those from Western countries, reviews on standardized treatment processes before and after endoscopic resection are nevertheless lacking. In this article we provide a narrative review of studies on the selection of appropriate EGC for endoscopic resection and the follow-up strategies for those with histologically confirmed EGC after endoscopic resection. EGC should be comprehensively assessed before endoscopic resection, including its exact margin, invasive depth and risk of lymph node metastasis (LNM). While the curative resection status of EGC may be evaluated after endoscopic resection based on the newly developed eCura system, although this needs to be further verified. Surveillance with endoscopy and computed tomography scan is necessary for patients with an EGC level A or B. An additional endoscopic resection is recommended for patients with a level-C1 EGC. For patients with a level-C2 EGC, close follow-up is suggested for low-risk tumors of level C2 and additional surgery for those at high risks. Further postoperative strategy is suggested based on comprehensive assessment of the risk of LNM, patient's quality of life and wishes.

RAB31 Targeted by MiR-30c-2-3p Regulates the GLI1 Signaling Pathway, Affecting Gastric Cancer Cell Proliferation and Apoptosis.

Background: Gastric cancer (GC), one of the most common cancers worldwide, is highly malignant and fatal. Ras-related protein in brain 31 (RAB31), a member of the RAB family of oncogenes, participates in the process of carcinogenesis and cancer development; however, its role in GC progression is unknown. Methods: In our study, 90 pairs of tissue microarrays were used to measure the levels of RAB31 protein by immunochemistry, and 22 pairs of fresh tissue were used to measure the levels of RAB31 mRNA by quantitative PCR. We also investigated the effects of RAB31 on tumor growth both in vitro and in vivo. Results: RAB31 was overexpressed in GC tissues, and its overexpression predicted poor survival in patients. In a nude mouse model, depletion of RAB31 inhibited tumor growth. In vitro, silencing of RAB31 suppressed cell viability, promoted cell cycle arrest, enhanced apoptosis, and affected the expression of cell cycle and apoptotic proteins; these effects were mediated by glioma-associated oncogene homolog 1 (GLI1). Co-immunoprecipitation and immunofluorescence assays confirmed that RAB31 interacted with GLI1. In addition, luciferase reporter assays and Western blotting showed that microRNA-30c-2-3p modulated the RAB31/GLI1 pathway by targeting the 3'-untranslated region of RAB31. Conclusions: Collectively, these data show that RAB31 is regulated by microRNA-30c-2-3p, and functions as an oncogene in GC tumorigenesis and development by interacting with GLI1. Therefore, targeting the miR-30c-2-3p/RAB31/GLI1 axis may be a therapeutic intervention for gastric cancer.

NOX4, a new genetic target for anti-cancer therapy in digestive system cancer.

Oxidative stress has been implicated as an important factor in tumorigenesis and tumor progression. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 4 (NOX4), a substrate of NADPH that can generate H2 O2 reactive oxygen species, has been reported to be highly expressed in gastrointestinal tumors. In this review we summarize the available evidence on the biological function of NOX4 in digestive system tumors by focusing on its correlation with classical cell signaling pathways, including VEGF, MAPK and PI3K/AKT, and with biochemical mediators, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein (AP)-1 and transforming growth factor (TGF)-ß. According to the clinical and database studies on tumors of the digestive system, such as colorectal, gastric and pancreatic cancer, there are significant associations between NOX4 expression and tumor prognosis as well as patient's survival. Animal studies using NOX4 inhibitors such as diphenylene iodonium and GKT137831, which selectively block NOX4, indicate their potential as therapeutic agents for targeting cancer cells.

NOX4-driven ROS formation regulates proliferation and apoptosis of gastric cancer cells through the GLI1 pathway.

NADPH Oxidase 4 (NOX4), a member of the NOX family, has emerged as a significant source of reactive oxygen species, playing an important role in tumor cell proliferation, apoptosis, and other physiological processes. However, the potential function of NOX4 in gastric cancer (GC) cell proliferation is yet unknown. The aim of this study was to illustrate whether NOX4 plays a role in regulating gastric cancer cell growth. First, the clinical information from 90 patients was utilized to explore the clinical value of NOX4 as a predictive tool for tumor size and prognosis. Results showed that NOX4 expression was correlated with tumor size and prognosis. In vitro assays confirmed that knockdown of NOX4 expression blocked cell proliferation and the expression of Cyclin D1, BAX, and so on. Interestingly, NOX4 promoted cell proliferation via activation of the GLI1 pathway. GLI1, a well-known transcription factor in the Hedgehog signaling pathway, was overexpressed to test whether NOX4 activates downstream signaling via GLI1. Overexpression of GLI1 reversed the inhibition of proliferation induced by NOX4 knockdown. In addition, overexpression of NOX4 increased GLI1 expression, and depletion of GLI1 expression decreased the effects induced by NOX4 overexpression. Further, ROS generated by NOX4 was required for GLI1 expression, as shown by use of the ROS inhibitor, diphenylene iodonium (DPI). In summary, the findings indicate that NOX4 plays an important role in gastric cancer cell growth and apoptosis through the generation of ROS and subsequent activation of GLI1 signaling. Hence, the targeting of NOX4 may be an attractive therapeutic strategy for blocking gastric cancer cell proliferation.

Pseudopod-associated protein KIF20B promotes Gli1-induced epithelial-mesenchymal transition modulated by pseudopodial actin dynamic in human colorectal cancer.

Kinesin family member 20B (KIF20B) has been reported to have an oncogenic role in bladder and hepatocellular cancer cells, but its role in colorectal cancer (CRC) progression remains unclear. In this study, we assessed the mRNA and protein levels of KIF20B in CRC tissues using qRT-PCR and immunohistochemistry, respectively. KIF20B was overexpressed in CRC tissues and was associated with cancer invasion and metastasis. Mechanistically, KIF20B overexpression promoted the epithelial-mesenchymal transition (EMT) process mediated by glioma-associated oncogene 1 (Gli1) as well as CRC cell migration and invasion. Interestingly, KIF20B was localized in pseudopod protrusions of CRC cells and influenced the formation of cell protrusions, especially the EMT-related invadopodia. Moreover, intracellular actin dynamic participated in the modulation of the Gli1-mediated EMT and EMT-related cell pseudopod protrusion formation induced by KIF20B. We identified a role for KIF20B in CRC progression and revealed a correlation between KIF20B expression in CRC tissues and patient prognosis. The underlying mechanism was associated with the Gli1-mediated EMT and EMT-related cell protrusion formation modulated by intracellular actin dynamic. Thus, KIF20B may be a potential biomarker and promising treatment target for CRC.

High expression of GPR116 indicates poor survival outcome and promotes tumor progression in colorectal carcinoma.

Previous studies have found that G-protein-coupled receptor 116 (GPR116) is a regulator of breast cancer metastasis. However, the role of GPR116 in colorectal carcinoma (CRC) carcinogenesis and progression is unknown. In this study, We found GPR116 expression was significantly up-regulated in CRC specimens compared with corresponding non-cancerous tissues. Increased GPR116 expression in CRC was correlated with histological differentiation and distant metastasis. In addition, high expression of GPR116 was significantly associated with poor overall survival of CRC patients, which was also confirmed by GSE14333, GSE17536 and GSE33113 datasets from the Gene Expression Omnibus (GEO). Furthermore, we demonstrated that the ability of proliferation and invasion of CRC cell lines HCT116 and LOVO was markedly reduced after transfected with siRNA-GPR116. Meanwhile, GPR116 may drive EMT in CRC cells through AKT/EKR signaling pathway, resulting in metastasis. Thus, GPR116 may be a novel reliable prognostic indicator and a risk factor in CRC progression.

Overexpression of NOX4 predicts poor prognosis and promotes tumor progression in human colorectal cancer.

NADPH oxidase 4 (NOX4), a major source of reactive oxygen species (ROS) production, has been increasingly reported to be involved in tumorigenesis and/or tumor progression, but limited data are available regarding the role of NOX4 in colorectal carcinoma (CRC). We retrieved six independent investigations from Oncomine database and found that NOX4 is highly expressed in CRC tissues compared with corresponding normal controls. Similar results were also found in clinical specimens at both mRNA and protein levels. Immunohistochemical analysis indicated that NOX4 overexpression was highly correlated with T classification, N classification, distant metastasis, and poor prognosis of CRC patients, which was also confirmed by GSE14333 and GSE17536 datasets from the Gene Expression Omnibus. Furthermore, we demonstrated that when NOX4 expression was knocked down by siRNAs, cell proliferation, cell-cycle and apoptosis, migration and invasion were significantly altered in CRC cell lines HCT116 and LOVO. Meanwhile, NOX4 promoted cancer cell proliferation and apoptosis, migration and invasion by regulating the expression of relevant genes. By these approaches we aim to elucidate NOX4 may be a reliable prognostic factor or therapeutic target in CRC.