Predictors of difficult endoscopic resection of submucosal tumors originating from the muscularis propria layer at the esophagogastric junction.

BACKGROUND: Endoscopic resection approaches, including endoscopic submucosal dissection (ESD), submucosal tunneling endoscopic resection (STER) and endoscopic full-thickness resection (EFTR), have been widely used for the treatment of submucosal tumors (SMTs) located in the upper gastrointestinal tract. However, compared to SMTs located in the esophagus or stomach, endoscopic resection of SMTs from the esophagogastric junction (EGJ) is much more difficult because of the sharp angle and narrow lumen of the EGJ. SMTs originating from the muscularis propria (MP) in the EGJ, especially those that grow extraluminally and adhere closely to the serosa, make endoscopic resection even more difficult. AIM: To investigate the predictors of difficult endoscopic resection for SMTs from the MP layer at the EGJ. METHODS: A total of 90 patients with SMTs from the MP layer at the EGJ were included in the present study. The difficulty of endoscopic resection was defined as a long procedure time, failure of en bloc resection and intraoperative bleeding. Clinicopathological, endoscopic and follow-up data were collected and analyzed. Statistical analysis of independent risks for piecemeal resection, long operative time, and intraoperative bleeding were assessed using univariate and multivariate analyses. RESULTS: According to the location and growth pattern of the tumor, 44 patients underwent STER, 14 patients underwent EFTR, and the remaining 32 patients received a standard ESD procedure. The tumor size was 20.0 mm (range 5.0-100.0 mm). Fourty-seven out of 90 lesions (52.2%) were regularly shaped. The overall en bloc resection rate was 84.4%. The operation time was 43 min (range 16-126 min). The intraoperative bleeding rate was 18.9%. There were no adverse events that required therapeutic intervention during or after the procedures. The surgical approach had no significant correlation with en bloc resection, long operative time or intraoperative bleeding. Large tumor size (≥ 30 mm) and irregular tumor shape were independent predictors for piecemeal resection (OR: 7.346, P = 0.032 and OR: 18.004, P = 0.029, respectively), long operative time (≥ 60 min) (OR: 47.330, P = 0.000 and OR: 6.863, P = 0.034, respectively) and intraoperative bleeding (OR: 20.631, P = 0.002 and OR: 19.020, P = 0.021, respectively). CONCLUSION: Endoscopic resection is an effective treatment for SMTs in the MP layer at the EGJ. Tumors with large size and irregular shape were independent predictors for difficult endoscopic resection.

Comparison of Pull and Introducer Techniques for Percutaneous Endoscopic Gastrostomy.

Objective: To compare indications, success rates and complications of pull [P] and introducer [I] techniques for percutaneous endoscopic gastrostomy (PEG). Methods: In this retrospective study, inpatients who underwent primary PEG tube insertion between January 2015 and February 2020 at the Endoscopy Center of the First Affiliated Hospital of Fujian Medical University were included. Results: A total of 103 inpatients were included in this study (P group, n = 67; I group, n = 36). The rates of tube replacement within first six months in the P and I groups were 1.5% and 11.1%, respectively (P = 0.049). The most common primary indication of PEG was malignancy. The proportion of patients with esophageal cancer was significantly lower in the P group (24.4% vs 54.2%, P = 0.015). No significant difference was found in the overall, major, or minor complications between the two groups. In patients with esophageal stenosis, the pull method was a risk factor for complications (P = 0.03; odds ratio [OR] = 12, 95% confidence interval [CI]: 1.164-123.684). Logistic regression analysis showed that the risk factors for major and minor complications were the admission-to-gastrostomy interval (OR = 1.078, 95% CI: 1.016-1.145, P = 0.014) and lack of antibiotic use (OR = 4.735, 95% CI: 1.247-17.979, P = 0.022), respectively. Conclusion: Both PEG techniques have high clinical success rates. The introducer technique is more suitable for patients with esophageal stricture, which has lower minor complications, but higher rate of tube replacement compared to the pull technique. Use of antibiotics may reduce minor complications following PEG. Early PEG insertion may help to reduce post-PEG major complications.

lncRNA FOXP4­AS1 predicts poor prognosis and accelerates the progression of mantle cell lymphoma through the miR­423­5p/NACC1 pathway.

Long non­coding RNA (lncRNA) forkhead box P4 antisense RNA 1 (FOXP4­AS1) has been determined to function as an oncogene in various types of cancer. However, the biological function and the underlying mechanisms of FOXP4­AS1 in mantle cell lymphoma (MCL) remain to be uncovered. The expression and the associated clinicopathological characteristics and prognostic significance of FOXP4­AS1 were explored in MCL clinical samples. The effects of FOXP4­AS1 on MCL cellular behaviors, including proliferation, migration and invasion were analyzed using CCK­8, crystal violet and Transwell assays. The downstream molecules of FOXP4­AS1 were explored using bioinformatics analysis and dual luciferase assay. Our results showed that FOXP4­AS1 expression was upregulated in MCL patients, and that the high expression of FOXP4­AS1 was correlated with the unfavorable prognosis of patients. Functionally, while FOXP4­AS1 downregulation inhibited proliferation, migration and invasion of MCL cells, FOXP4­AS1 overexpression had promotive effects on these cellular processes. Mechanistically, FOXP4­AS1 was found to act as a competing endogenous (ce)RNA for miR­423­5p to regulate the expression of nucleus accumbens­associated 1 (NACC1). The negative regulation of FOXP4­AS1 on miR­423­5p compared to that of miR­423­5p on NACC1 was determined at the mRNA or protein levels in MCL cells. Moreover, an inverse expression correlation between FOXP4­AS1 and miR­423­5p, and that between miR­423­5p and NACC1 was confirmed in MCL clinical samples. In addition, rescue assay showed that miR­423­5p upregulation or NACC1 knockdown abolished the promoting effects of FOXP4­AS1 on MCL cell proliferation, migration and invasion. In conclusion, FOXP4­AS1 promotes MCL progression through the upregulation of NACC1 expression by inhibiting miR­423­5p. FOXP4­AS1 may serve as a novel therapeutic target for patients with MCL.

The Tumor Suppressive Roles and Prognostic Values of STEAP Family Members in Breast Cancer.

OBJECTIVE: To investigate the expression patterns and prognostic values of STEAP family members in the occurrence and development of breast cancer. MATERIALS AND METHODS: The Human Protein Atlas was used to analyze the expression level of STEAPs in human normal tissues and malignant tumors. ONCOMINE datasets were analyzed for the comparison of the STEAPs levels between malignant cancers and corresponding normal tissues. Kaplan-Meier plotter was used to analyze the prognostic value of STEAPs in breast cancer patients. RESULTS: STEAPs were widely distributed in human normal tissues with diverse levels. Normally, it is predicted that STEAP1 and STEAP2 were involved in the mineral absorption process, while STEAP3 participated in the TP53 signaling pathway and iron apoptosis. The results from ONCOMINE showed downregulation of STEAP1, STEAP2, and STEAP4 in breast cancers. Survival analysis revealed that breast cancer patients with high levels of STEAP1, STEAP2, and STEAP4 had a good prognosis, while those with low expression had high overall mortality. CONCLUSION: STEAP1, STEAP2, and STEAP4 are predicted to be the potential prognostic biomarkers for breast cancer patients, providing novel therapeutic strategies for them.

Involvement of glutathione peroxidases in the occurrence and development of breast cancers.

Glutathione peroxidases (GPxs) belong to a family of enzymes that is important in organisms; these enzymes promote hydrogen peroxide metabolism and protect cell membrane structure and function from oxidative damage. Based on the establishment and development of the theory of the pathological roles of free radicals, the role of GPxs has gradually attracted researchers' attention, and the involvement of GPxs in the occurrence and development of malignant tumors has been shown. On the other hand, the incidence of breast cancer in increasing, and breast cancer has become the leading cause of cancer-related death in females worldwide; breast cancer is thought to be related to the increased production of reactive oxygen species, indicating the involvement of GPxs in these processes. Therefore, this article focused on the molecular mechanism and function of GPxs in the occurrence and development of breast cancer to understand their role in breast cancer and to provide a new theoretical basis for the treatment of breast cancer.

Long non-coding RNAs engender drug resistance to different subtypes of treatments of breast cancers and may provide a "next generation" therapy option.

The dysfunction of long non-coding RNAs (lncRNAs), without protein-coding potential, has been implicated in drug resistance against treatment in various human diseases, especially in malignant tumors. As the most common-diagnosed female malignancy worldwide, breast cancer is also the second-leading cause of cancer-related mortality in women. Despite the improvement in neo-adjuvant therapy, endocrine therapy, molecular-targeted treatment, and chemotherapy, drug resistance to various treatment regimens is still quite prevalent. This article focused on the lncRNAs and their functions in drug resistance against breast cancer therapeutic agents, in order to develop new precise treatment strategies for patients with breast cancers. The discovery of lncRNA opened new doors to the molecular mechanisms of the biological processes, and has provided new pathways to regulate biochemical events. Thus, lncRNAs may be developed as a biomarker for the detection and/or prevention of breast cancer. Additionally, lncRNA-based approaches may provide an additional treatment modality in personalized medicine alone or in combination with existing tumor-directed interventions to improve patient outcomes. In conclusion, lncRNAs molecules may represent the "next generation" therapy option for breast cancer patients.

Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer.

Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc finger-homeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-ß, ß-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.

Analysis of the Differentially Expressed Genes Induced by Cisplatin Resistance in Oral Squamous Cell Carcinomas and Their Interaction.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a solid tumor, which originates from squamous epithelium, with about 400,000 new-cases/year worldwidely. Presently, chemoradiotherapy is the most important adjuvant treatment for OSCC, mostly in advanced tumors. However, clinical resistance to chemotherapy still leads to poor prognosis of OSCC patients. Via high-throughput analysis of gene expression database of OSCC, we investigated the molecular mechanisms underlying cisplatin resistance in OSCC, analyzing the differentially expressed genes (DEGs) and their regulatory relationship, to clarify the molecular basis of OSCC chemotherapy resistance and provide a theoretical foundation for the treatment of patients with OSCC and individualized therapeutic targets accurately. METHODS: Datasets related to "OSCC" and "cisplatin resistance" (GSE111585 and GSE115119) were downloaded from the GEO database and analyzed by GEO2R. Venn diagram was used to obtain drug-resistance-related DEGs. Functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed on DEGs using The Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Protein-protein interaction (PPI) network was constructed by STRING (search tool for recurring instances of neighbouring genes) database. Potential target genes of miRNA were predicted via miRDB, and cBioportal was used to analyze the function and survival of the potential functional genes. RESULTS: Forty-eight upregulated DEGs and 49 downregulated DEGs were obtained from the datasets, with cutoff as p < 0.01 and |log FC| > 1. The DEGs in OSCC mainly enriched in cell proliferation regulation, and chemokine activity. In PPI network with hub score > 300, the hub genes were identified as NOTCH1, JUN, CTNNB1, CEBPA, and ETS1. Among miRNA-mRNA targeting regulatory network, hsa-mir-200c-3p, hsa-mir-200b-3p, hsa-mir-429, and hsa-mir-139-5p were found to simultaneously regulate multiple hub genes. Survival analysis showed that patients with high CTNNB1 or low CEBPA expression had poor outcome. CONCLUSIONS: In the OSCC cisplatin-resistant cell lines, NOTCH1, JUN, CTNNB1, CEBPA, and ETS1 were found as the hub genes involved in regulating the cisplatin resistance of OSCC. Members of the miR-200 family may reverse drug resistance of OSCC cells by regulating the hub genes, which can act as potential targets for the treatment of OSCC patients with cisplatin resistance.

Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target.

PURPOSE: Extracellular matrix (ECM) is an important component of tumor microenvironment and plays critical roles in cancer development and metastasis, in which collagen is the major structural protein. Collagen type I alpha 1 (COL1A1) is reportedly associated with the development of several human diseases. However, the functions and mechanisms of cellular expression of COL1A1 in breast cancer remain unknown. The purpose of this study is to investigate the cellular expression of COL1A1 in breast cancer cells and patients, and its role in the development and metastasis of breast cancer. METHODS: The immunofluorescence staining was used to identify the cellular location of COL1A1 in breast cancer cell lines. Real-time PCR was applied to measuring the mRNA levels of COL1A1 and genes of interest. Wound healing and transwell assay were performed to evaluate the effect of COL1A1 on metastasis of breast cancer cells. 97 patients with breast cancer were recruited in this study for evaluating the correlation of COL1A1 with survival and clinicopathological parameters. RESULTS: COL1A1 was expressed in all examined breast cancer cells. Knockdown of COL1A1 inhibited metastasis of breast cancer cells, with a low-level of CXCR4, independent of the epithelial-mesenchymal transition (EMT) process. In patients with breast cancer, cellular expression of COL1A1 was associated with ER/PR expression and metastasis status. The increased COL1A1 level was associated with poor survival, especially in patients with ER+ breast cancer. Patients with a high-level of COL1A1 showed better cisplatin-based chemotherapy response. CONCLUSION: Cellular expression of COL1A1 could promote breast cancer metastasis. COL1A1 is a new prognostic biomarker and a potential therapeutic target for breast cancer, especially in ER+ patients.

Bioluminescence Imaging for Monitoring miR-200c Expression in Breast Cancer Cells and its Effects on Epithelial-Mesenchymal Transition Progress in Living Animals.

PURPOSE: Dysregulation of microRNAs (miRNAs) are not only involved in the formation of malignant tumors but also in the processes of differentiation and aggressiveness. However, current methods for detecting miRNA expression have major disadvantages, such as being invasive and non-reproducible. The epithelial-mesenchymal transition (EMT) has been implicated as a pivotal event in the metastasis, stemness, and chemoresistance of malignant tumors. PROCEDURES: In our study, we constructed a new reporter gene, Luc2/tdT_miR200c_3TS, to examine the in vitro and in vivo expression of miR-200c, an EMT-associated miRNA. Quantitative real-time PCR was used to measure the expression levels of miR-200c and EMT-related mRNA, and luciferase assay and bioluminescence imaging were used to measure the luciferase activities in vitro and in vivo, respectively. RESULTS: We found that the expression level of miR-200c was negatively associated with cell migration and invasion. Luciferase activities were regulated by the differential expression levels of miR-200c and EMT process. CONCLUSIONS: Our results demonstrate that Luc2/tdT_miR200c_3TS may be a useful tool for monitoring the expression level of miR-200c at both the cellular level and in living animals, thereby providing a potential high-throughput approach for anticancer drug screening.

Interleukin-33 in Malignancies: Friends or Foes?

The human Interleukin-33 (IL-33), a member of the IL-1 family, is the cytokine as a cell endogenous alarmin, released by damaged or necrotic barrier cells (endothelial and epithelial cells). The signal transduction of IL-33 relies on recognition and interaction with specific receptor ST2, mainly expressed in immune cells. In both innate and adoptive immunity, IL-33 regulates the homeostasis in response to stress from within/out the microenvironment. Various, even negative biofunctions of IL-33 pathways have now been widely verified in pathogenesis among immunological mechanisms, like Th2-related immune-stimuli, inflammation/infection-induced tissue protectors. A larger versatility in studies of IL-33 on malignancies now focuses on: (1) promoting myeloid-derived suppressor cells (MDSC), (2) intervention toward CD8+ T, Natural Killer (NK) cell infiltration, group 2 innate lymphoid cells (ILC2) proliferation, dendritic cells (DC) activation, and (3) inhibiting tumor growth and/or further metastasis as an immunoadjuvant. Although IL-33 functioned pro-tumorigenically in various cancers, for some cancer types the findings so far are controversial. This review begins from a summarized introduction of IL-33, to its remarkable implications and molecular transduction pathway in malignant neoplasms, ends with latest inspiration for IL-33 in treatment.

The transcriptional STAT3 is a potential target, whereas transcriptional STAT5A/5B/6 are new biomarkers for prognosis in human breast carcinoma.

Signal Transducer and Activators of Transcription (STAT) is a set of transcription factors, involved in diverse cellular functions. Evidences from cell lines, mouse models and human tissues implicate these transcription factors in the oncogenesis of breast cancer. However, the diverse expression patterns and prognostic values of 7 STATs remain to be elucidated. In the current study, we mined the transcriptional and survival data of STATs in patients with breast carcinoma (BC) through ONCOMINE, bc-GenExMiner, Kaplan-Meier Plotter and cBioPortal. It was found that STAT1/2 were up-regulated, whereas STAT3/4/5A/5B were down-regulated in BC patients compared with the normal tissues. The expressions of STAT5A/5B/6 were correlated with decreased levels of histological differentiation. In survival analyses through the Kaplan-Meier plotter database, high transcription levels of STAT2/4/5A/5B/6 were associated with better relapse-free survival (RFS) in all BC patients. Conversely, high STAT3 predicted shorter RFS in BC patients, suggesting that STAT3 is potential targets for precision therapy to BC patients. These data also provided STAT5A/5B/6 as new biomarker for BC prognosis.

Targeting Notch degradation system provides promise for breast cancer therapeutics.

Notch receptor signaling pathways play an important role, not only in normal breast development but also in breast cancer development and progression. As a group of ligand-induced proteins, different subtypes of mammalian Notch (Notch1-4) are sensitive to subtle changes in protein levels. Thus, a clear understanding of mechanisms of Notch protein turnover is essential for understanding normal and pathological mechanisms of Notch functions. It has been suggested that there is a close relationship between the carcinogenesis and the dysregulation of Notch degradation. However, this relationship remains mostly undefined in the context of breast cancer, as protein degradation is mediated by numerous signaling pathways as well as certain molecule modulators (activators/inhibitors). In this review, we summarize the published data regarding the regulation of Notch family member degradation in breast cancer, while emphasizing areas that are likely to provide new therapeutic modalities for mechanism-based anti-cancer drugs.

Mining distinct aldehyde dehydrogenase 1 (ALDH1) isoenzymes in gastric cancer.

Aldehyde dehydrogenase 1 (ALDH1) consists of a family of intracellular enzymes, highly expressed in stem cells populations of leukemia and some solid tumors. Up to now, 6 isoforms of ALDH1 have been reported. However, the expression patterns and the identity of ALDH1 isoenzymes contributing to ALDH1 activity, as well as the prognostic values of ALDH1 isoenzymes in cancers all remain to be elucidated. Here, we studied the expressions of ALDH1 transcripts in gastric cancer (GC) compared with the normal controls using the ONCOMINE database. Through the Kaplan-Meier plotter database, which contains updated gene expression data and survival information of 876 GC patients, we also investigated the prognostic values of ALDH1 isoenzymes in GC patients. It was found that when compared with normal tissues, ALDH1A1 mRNA expression was downregulated, whereas ALDH1A3 and ALDH1B1 were upregulated in GC patients. In survival analyses, high ALDH1A1 and ALDH1B1 expressions were associated with better overall survival (OS) in all GC patients. In addition, high transcription activity of ALDH1A1 predicted better OS in gastric intestinal type adenocarcinoma, but not in diffuse gastric adenocarcinoma. GC patients with high mRNA level of ALDH1B1 showed better OS in gastric intestinal type, and worse OS in diffuse type. Oppositely, high transcription activities of ALDH1A2, ALDH1A3 and ALDH1L1 predicted worsen overall survival in GC patients, suggesting that these isoenzymes might be responsible mainly for the ALDH1 activities in GC. These data provides ALDH1A2, ALDH1A3 and ALDH1L1 as excellent potential targets for individualized treatment of GC patients.

Significance of interleukin-33 and its related cytokines in patients with breast cancers.

Interleukin-33 (IL-33) is a recently identified cytokine, an important member of the interleukin-1 family. IL-33 binds to its receptor ST2 to induce type 2 cytokines and exert both pro-inflammatory and protective functions in host defense and disease. Murine breast carcinoma models suggest disruption of ST2 signaling may enhance the anti-tumor immune response, suggesting IL-33 impedes anti-tumor immunity. However, the role of IL-33 in patients with breast cancers (BC) is not elucidated. We detected the expression of IL-33 in tumor tissue, and IL-33 and its related cytokines in serum from BC patients. Using Luminex and immunohistochemistry methods, we found that serum levels of IL-33 were nearly twofold higher in patients with BC, compared to patients with benign breast diseases. In cancer tissues, expression of IL-33 was higher than matched normal breast tissues from the same patients, and was also associated with a well-differentiated phenotype, HER2 overexpression, more lymph nodes involvement, and a family history of malignant carcinoma. These results suggest that IL-33 may play an important role in the progress of BC and may be a useful biomarker for predicting the progress and metastasis of BC.