Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial.

BACKGROUND: The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population. METHODS: RLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m2), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4-6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform. RESULTS: Of the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity. CONCLUSIONS: Combining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients. TRIAL REGISTRATION NUMBER: ChiCTR2100045104.

Circulating tumor DNA integrating tissue clonality detects minimal residual disease in resectable non-small-cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has been proven as a marker for detecting minimal residual diseases following systemic therapies in mid-to-late-stage non-small-cell lung cancers (NSCLCs) by multiple studies. However, fewer studies cast light on ctDNA-based MRD monitoring in early-to-mid-stage NSCLCs that received surgical resection as the standard of care. METHODS: We prospectively recruited 128 patients with stage I-III NSCLCs who received curative surgical resections in our Lung Cancer Tempo-spatial Heterogeneity prospective cohort. Plasma samples were collected before the surgery, 7 days after the surgery, and every 3 months thereafter. Targeted sequencing was performed on a total of 628 plasma samples and 645 matched tumor samples using a panel covering 425 cancer-associated genes. Tissue clonal phylogeny of each patient was reconstructed and used to guide ctDNA detection. RESULTS: The results demonstrated that ctDNA was more frequently detected in patients with higher stage diseases pre- and postsurgery. Positive ctDNA detection at as early as 7 days postsurgery identified high-risk patients with recurrence (HR = 3.90, P < 0.001). Our results also show that longitudinal ctDNA monitoring of at least two postsurgical time points indicated a significantly higher risk (HR = 7.59, P < 0.001), preceding radiographic relapse in 73.5% of patients by a median of 145 days. Further, clonal ctDNA mutations indicated a high-level specificity, and subclonal mutations informed the origin of tumor recurrence. CONCLUSIONS: Longitudinal ctDNA surveillance integrating clonality information may stratify high-risk patients with disease recurrence and infer the evolutionary origin of ctDNA mutations.

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.

Background: Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD). Methods: Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2. Results: BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming. Conclusions: In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.

The application value of preoperative fat-free mass index within Global Leadership Initiative on Malnutrition-defined malnutrition criteria for postoperative outcomes in patients with esophagogastric cancer.

OBJECTIVE: The present study aimed to investigate the prognostic value of the preoperative fat-free mass index (FFMI) for postoperative outcomes in patients undergoing esophagogastric cancer surgery and to explore the role of the FFMI in the Global Leadership Initiative on Malnutrition (GLIM) criteria. METHODS: This multicenter retrospective observational study took place in four teaching tertiary hospitals in China from September 2015 to June 2018. Malnutrition was diagnosed following the GLIM criteria. The evaluation of muscle mass (ie, the FFMI) as one of the constituents contained in the GLIM consensus was measured by bioelectrical impedance analysis. According to their FFMI per the GLIM criteria, patients with esophagogastric cancer were divided into a normal-FFMI group and a low-FFMI group. The observation indicators were postoperative complications, length of stay, wound healing time, postoperative antibiotic time, and nutritional status in the two groups. RESULTS: Of the 205 total patients with esophagogastric cancer, 76 (37.1%) were diagnosed with malnutrition. The normal-FFMI group had a significantly lower rate of postoperative complications (43 [33.3%] of 129 patients versus 37 [48.7%] of 76 patients; P = 0.038) and a shorter postoperative length of stay (12.6 ± 3.1 d versus 14.3 ± 3.2 d; P = 0.034), postoperative antibiotic time (5.3 ± 2.9 d versus 6.4 ± 2.1 d; P = 0.031), and wound healing time (10.9 ± 2.5 d versus 11.9 ± 3.1 d; P = 0.005) compared with the low-FFMI group. There were no significant differences between the groups in rates of other clinical outcomes. The body mass index (BMI) and FFMI were generally consistent in the diagnosis of malnutrition based on GLIM criteria (kappa, 0.464; P < 0.001). The linear correlation between BMI and FFMI (correlation coefficient, 0.659; P < 0.001) was moderate in patients with esophagogastric cancer who were at nutritional risk. CONCLUSIONS: The FFMI has an important role in the diagnosis of malnutrition using the GLIM criteria. In this study, a decreased preoperative FFMI was closely associated with postoperative complications in patients with esophagogastric cancer.

Association between delta anion gap and hospital mortality for patients in cardiothoracic surgery recovery unit: a retrospective cohort study.

BACKGROUNDS: High level of anion gap (AG) was associated with organic acidosis. This study aimed to explore the relationship between delta AG (ΔAG = AGmax - AGmin) during first 3 days after intensive care unit (ICU) admission and hospital mortality for patients admitted in the cardiothoracic surgery recovery unit (CSRU). METHODS: In this retrospective cohort study, we identified patients from the open access database called Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC III). A logistic regression model was established to predict hospital mortality by adjusting confounding factors using a stepwise backward elimination method. We conducted receiver operating characteristic (ROC) curves to compare the diagnostic performance of acid-base variables. Cox regression model and Kaplan Meier curve were applied to predict patients' 90-day overall survival (OS). RESULTS: A total of 2,860 patients were identified. ΔAG was an independent predictive factor of hospital mortality (OR = 1.24 per 1 mEq/L increase, 95% CI: 1.11-1.39, p < 0.001). The area under curve (AUC) values of ΔAG suggested a good diagnostic accuracy (AUC = 0.769). We established the following formula to estimate patients' hospital mortality: Logit(P) = - 15.69 + 0.21ΔAG + 0.13age-0.21BE + 2.69AKF. After calculating Youden index, patients with ΔAG ≥ 7 was considered at high risk (OR = 4.23, 95% CI: 1.22-14.63, p = 0.023). Kaplan Meier curve demonstrated that patients with ΔAG ≥ 7 had a poorer 90-day OS (Adjusted HR = 3.20, 95% CI: 1.81-5.65, p < 0.001). CONCLUSION: ΔAG is a prognostic factor of hospital mortality and 90-day OS. More prospective studies are needed to verify and update our findings.

An integrated analysis of prognostic and immune infiltrates for hub genes as potential survival indicators in patients with lung adenocarcinoma.

OBJECTIVE: Lung adenocarcinoma (LUAD) is one of the major subtypes of lung cancer that is associated with poor prognosis. The aim of this study was to identify useful biomarkers to enhance the treatment and diagnosis of LUAD. METHODS: GEO2R was used to identify common up-regulated differentially expressed genes (DEGs) in the GSE32863, GSE40791, and GSE75037 datasets. The DEGs were submitted to Metascape for gene ontology and pathway enrichment analysis as well as construction of the protein-protein interaction (PPI) network, while the molecular complex detection (MCODE) plug-in was employed to filter important subnetworks. The expression levels of the hub genes and their prognostic values were evaluated using the UALCAN, GEPIA2, and Kaplan-Meier plotter databases. The timer algorithm was utilized to determine the correlation between immune cell infiltration and the expression levels of hub genes in LUAD tissues. In addition, the hub gene mutation landscape and the correlation analysis with tumor mutational burden (TMB) score were evaluated using maftools package and ggstatsplot package in R software, respectively. RESULTS: We identified 156 common up-regulated DEGs, with gene ontology and pathway enrichment analysis indicating that they were mostly enriched in mitotic cell cycle process and cell cycle pathway. DEGs in the subnetwork with the largest number of genes were AURKB, CCNB2, CDC20, CDCA5, CDCA8, CENPF, and KNTC1. The seven hub genes were highly expressed in LUAD tissues and were associated with poor prognosis. These hub genes were negatively correlated with most immune cells. The somatic mutation landscape showed that AURKB, CDC20, CENPF, and KNTC1 had mutations and were positively correlated with TMB scores. CONCLUSIONS: Our findings demonstrate that increased expression of seven hub genes is associated with poor prognosis for LUAD patients. Additionally, the TMB score indicates that the high expression of hub gene increases immune cell infiltration in patients with lung adenocarcinoma which may significantly improve response to immunotherapy.

lncRNA GAS6-AS1 inhibits progression and glucose metabolism reprogramming in LUAD via repressing E2F1-mediated transcription of GLUT1.

Glucose metabolism reprogramming is one of the hallmarks of cancer cells, although functional and regulatory mechanisms of long noncoding RNA (lncRNA) in the contribution of glucose metabolism in lung adenocarcinoma (LUAD) remain incompletely understood. The aim of this study was to uncover the role of GAS6-AS1 in the regulation of progression and glucose metabolism in LUAD. We discovered that overexpression of GAS6-AS1 suppressed tumor progression of LUAD both in vitro and in vivo. Metabolism-related assays revealed that GAS6-AS1 inhibited glucose metabolism reprogramming. Mechanically, GAS6-AS1 was found to repress the expression of glucose transporter GLUT1, a key regulator of glucose metabolism. Ectopic expression of GLUT1 restored the inhibition effect of GAS6-AS1 on cancer progression and glucose metabolism reprogramming. Further investigation identified that GAS6-AS1 directly interacted with transcription factor E2F1 and suppressed E2F1-mediated transcription of GLUT1, and GAS6-AS1 was downregulated in LUAD tissues and correlated with clinicopathological characteristics and survival of patients. Taken together, our results identified GAS6-AS1 as a novel tumor suppressor in LUAD and unraveled its underlying molecular mechanism in reprogramming glucose metabolism. GAS6-AS1 potentially may serve as a prognostic marker and therapeutic target in LUAD.

A bibliometric analysis of segmentectomy versus lobectomy for non-small cell lung cancer research (1992-2019).

BACKGROUND: This study intends to create a series of scientific maps to quantitatively estimate hot spots and emerging trends in segmentectomy versus lobectomy for non-small cell lung cancer (NSCLC) research with bibliometric methods. METHODS: Articles published on segmentectomy versus lobectomy for NSCLC were extracted from the Web of Science Core Collection (WoSCC). Extracted information was analyzed quantitatively using bibliometric analysis by CiteSpace to find hot spots and frontiers in this research area. RESULTS: A total of 362 scientific articles on segmentectomy versus lobectomy for NSCLC were collected, and the annual publication rate increased over time from 1992 to 2019. The leading country and the leading institution were the United States and University of Pittsburgh, respectively. Furthermore, the most prolific researchers were, namely, James D. Luketich, Rodney J. Landreneau, Matthew J. Schuchert, Morihito Okada, and David O. Wilson. The analysis of keywords pointed out that carcinoma, bronchogenic carcinoma, limited resection, segmental resection, and morbidity are hot spots and lymph node dissection, minimally invasive surgery, impact, epidemiology, and high risk are research frontiers in this field. CONCLUSION: Publications related to segmentectomy versus lobectomy for NSCLC have made great achievements based on bibliometric analysis in recent years. However, further research and global collaboration are still required. Finally, we find that segmentectomy for the treatment of NSCLC is receiving much more attention from researchers globally compared with lobectomy in this research area.

Esophageal cancer patients of heavier weight have more nutritional risk of inadequate calorie intake immediately after esophagectomy: a retrospective study.

BACKGROUND: Perioperative malnutrition is common in patients undergoing esophagectomy, and nutritional support is critical for postoperative recovery in these patients. But few studies reported which characteristics of these patients were associated with post-esophagectomy inadequate calorie intake. This study aimed to explore which patients were more likely to have inadequate calories immediately after esophagectomy and the impact on clinical outcomes. METHODS: From January 2018 to June 2019, patients undergoing esophagectomy were retrospectively divided into the "adequate calorie group" and the "inadequate calorie group" according to whether they met daily calorie requirements in a week after esophagectomy. Caloric requirements met rate and clinical outcomes were compared between patients with and without complications, and with weight > 70 kg or ≤ 70 kg. RESULTS: Patients in the inadequate calorie group (n = 104) had significantly higher weight (p < 0.001), lean body mass (p = 0.028), and BMI (p = 0.001) than the adequate calorie group (n = 46). Weight loss after esophagectomy was reduced (p = 0.043) in the adequate calorie group. Patients with complications had lower rate of adequate calorie intake (72.8% vs. 63.8%). The caloric requirements met rate in patients with weigh ≤ 70 kg was significantly higher than those weight > 70 kg (80.2% vs. 43.2%, p < 0.001). CONCLUSION: The weights of patients having inadequate calories in a week after esophagectomy were significantly heavier than those having adequate calories. Heavier patients after esophagectomy should attract more attention to their nutrition support. TRIAL REGISTRATION: This trial was registered ( ChiCTR1900025557 ).

MNX1 Promotes Malignant Progression of Cervical Cancer via Repressing the Transcription of p21cip1.

Motor neuron and pancreas homeobox 1 (MNX1) is a development-related genes and has been found to be highly expressed in several cancers. However, its biological function in cervical cancer remains largely unexplored. QRT-PCR, western blot, and IHC showed that MNX1 was abnormally overexpressed in cervical cancer tissues and cell lines. The high expression level of MNX1 correlated with poorer clinicopathologic characteristics in cervical cancer patients. Evaluated by RTCA (Real Time Cellular Analysis) proliferation assay, colony formation assay, EdU assay, transwell assay, and matrigel assay, we found that knockdown of MNX1 inhibited proliferation, migration and invasion of cervical cancer in vitro, while overexpression of MNX1 promoted malignant phenotype of cervical cancer. And subcutaneous xenograft model confirmed the malignant phenotype of MNX1 in vivo. Furthermore, flow cytometry, chromatin immunoprecipitation, and luciferase reporter assay indicated that MNX1 accelerated cell cycle transition by transcriptionally downregulating cyclin-dependent kinases p21cip1. In summary, our study revealed that MNX1 exerted an oncogenic role in cervical cancer via repressing the transcription of p21cip1 and thus accelerating cell cycle progression. Our results suggested that MNX1 was a potential diagnostic marker and therapeutic target for cervical cancer patients.

Application of Modified Tailed Microcoil in Preoperative Localization of Small Pulmonary Nodules: A Retrospective Study.

BACKGROUND: The localization of small pulmonary nodules (SPNs) during video-assisted thoracoscopic surgery (VATS) is challenging thoracic surgeon, especially in patients with severe pleural adhesion or visceral pleura pigmentation due to low success rate and future conversion to thoracotomy. This study aims to compare the efficacy and safety between modified microcoil and methylene blue in preoperative localization of small nodules, particularly patients with severe pleural adhesion or visceral pleura pigmentation. MATERIALS AND METHODS: From January 2018 to February 2019 in our institute, 342 patients who underwent computed tomography-guided localization of SPN were recruited in this retrospective cohort study and divided into the modified microcoil group (n = 239) and the methylene blue group (n = 103) according to the localization method. Clinical characteristics and perioperative complications were collected to analyze. RESULTS: All SPNs were successfully marked in both groups. Location-related complications, the duration of localization procedure, and the length of hospital stay were not different between the two groups. The operation time of modified microcoil and the duration of removal of nodule in operation were both shorter than the methylene blue (p = 0.014 and p = 0.047). The analysis stratified by gender showed that similar results were found in male patients (p = 0.01 and p = 0.00), while in female patients, no significant difference was found. Additionally, in senior patients (older than 60 years), the operation time in modified microcoil groups was less than methylene blue group (p = 0.024). CONCLUSION: Compared with methylene blue, modified microcoil achieved a shorter operation time of removal of nodule in VATS, especially for patients with pleural adhesion and the pigmentation of the lung surface as well as the male patients and the patients older than 60 years.

Synaptotagmin 12 (SYT12) Gene Expression Promotes Cell Proliferation and Progression of Lung Adenocarcinoma and Involves the Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Pathway.

BACKGROUND This study aimed to use bioinformatics analysis to compare data from tissue microarrays from patients with lung adenocarcinoma (LUAD) and normal lung tissue, and human lung adenocarcinoma cells with normal lung epithelial cells in vitro to investigate the role of synaptotagmin 12 (SYT12) gene expression in LUAD. MATERIAL AND METHODS Human lung adenocarcinoma cell lines (A549, SPC-A-1, H1299, H1975, and PC9) and the normal HBE cell line were compared, and tumor xenografts were developed in mice. The Cancer Genome Atlas (TCGA) tissue microarray data were used to compare SYT12 expression and overall survival (OS). The in vivo and in vitro effects of down-regulation and upregulation of SYT12 were studied using short-interfering RNA (si-RNA) and overexpression plasmids, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and Western blot investigated the molecular mechanisms of SYT12 expression in LUAD. RESULTS SYT12 expression was increased in tissues from patients with LUAD from TCGA and was associated with advanced tumor stage and reduced prognosis. Knockdown of SYT12 suppressed the proliferation and migration of LUAD cells, and upregulation of SYT12 increased the proliferation and migration of LUAD cells in vitro. Phosphorylation of PIK3R3 activated the PI3K/AKT/mTOR pathway. In the mouse xenograft model, expression of SYT12 increased the volume and weight of the xenograft tumors. CONCLUSIONS Bioinformatics analysis, human LUAD cells, and mouse xenograft studies showed that SYT12 acted as a possible oncogene by phosphorylation of PIK3R3 to activate the PI3K/AKT/mTOR signaling pathway.

Long Noncoding RNA Nuclear Paraspeckle Assembly Transcript 1 Promotes Progression and Angiogenesis of Esophageal Squamous Cell Carcinoma Through miR-590-3p/MDM2 Axis.

Angiogenesis has been identified as one of the hallmarks of cancer and aggravates cancer development and progression. Accumulating evidence indicated that long noncoding RNAs (lncRNAs) are powerful factors in regulating various cancer behaviors. The aim of this study is to verify the function and potential mechanisms of lncRNA NEAT1 in progression and angiogenesis of esophageal squamous cell carcinoma (ESCC). We found that NEAT1 was overexpressed in ESCC tissues and correlated with clinical characteristics of patients. Silence of NEAT1 inhibited proliferation, migration, invasion and angiogenesis of ESCC cells. High throughput sequencing and western blotting revealed that NEAT1 regulated MDM2/p53 pathway. Rescue of MDM2 restored the effect of NEAT1 on progression and angiogenesis of ESCC cells. Nude mice xenograft models further validated the role of NEAT1 in vivo. Importantly, NEAT1 functioned as a competing endogenous RNA for miR-590-3p to regulate MDM2 expression and miR-590-3p acted as a tumor suppressor in ESCC progression and angiogenesis. These findings suggested that NEAT1/miR-590-3p/MDM2 axis might serve as potential therapeutic targets for ESCC patients.

FAM111B, a direct target of p53, promotes the malignant process of lung adenocarcinoma.

Purpose: Lung adenocarcinoma (LUAD) is a main subtype of lung cancer, which is the leading cause of cancer-related deaths. The five-year survival rates of lung cancer patients are still comparatively low. Therefore, potential therapeutic targets are urgently needed to improve the survival of lung cancer patients. In this study, we identified FAM111B as an oncogene and potential therapeutic target for LUAD. Methods: The TCGA database and tissue microarray analysis were used to compare the expression of FAM111B in tumor tissue and normal tissues and evaluate the relationship between FAM111B expression and clinical survival. FAM111B was knocked down and overexpressed to observe whether FAM111B could affect the proliferation, migration, cell cycle, and apoptosis of LUAD cells in vivo and in vitro. Results: FAM111B was highly expressed in tumor tissues compared with normal tissues (P<0.01). LUAD patients with hyper-expression of FAM111B had a lower recurrence-free survival (P<0.01) and shorter overall survival (P<0.01). Knocking down FAM111B inhibited cell proliferation, migration and invasion in vitro and tumor growth in vivo. Silencing FAM111B could arrest LUAD cells at G2/M phase and increase apoptosis. Overexpression of FAM111B promoted the growth of lung cancer cells. FAM111B was identified as a direct target of p53 in existing researches by chip-seq analysis. Bioinformatics analysis predicted that FAM111B could directly bind to BAG3 (BCL2 associated athanogene 3). When FAM111B was down-regulated, both expression of BAG 3 and BCL2 were significantly reduced, whereas decreasing the expression of BAG3 had no effect on FAM111B. Conclusions: Our study indicated that FAM111B might be an oncogene and potential therapeutic target in LUAD which could be involved in the regulation of tumor cells by p53 signaling pathway and play an important role in the process of cell cycle and apoptosis by influencing the expression of BAG3 and BCL2.

DMBX1 promotes tumor proliferation and regulates cell cycle progression via repressing OTX2-mediated transcription of p21 in lung adenocarcinoma cell.

Lung adenocarcinoma (LUAD) was the predominant histological subtype of lung cancer, with poor prognosis. By analyzing the TCGA dataset, we found that DMBX1 (diencephalon/mesencephalon homeobox 1), a member of the bicoid sub-family of homeodomain-containing transcription factors, was overexpressed in LUAD and correlated with poorer prognosis and more advanced clinicopathological features of LUAD patients. Silencing of DMBX1 inhibited proliferation of LUAD and induced G1/S cell cycle arrest, whereas ectopic expression of DMBX1 enhanced tumor growth of LUAD and promoted G1/S cell cycle exit. Furtherly we found that the function of DMBX1 was dependent on p21 (CDKN1A), a key regulator of G1/S cell cycle progression. Co-IP assay revealed that DMBX1 directly bound to another homeobox transcription factor, OTX2. ChIP and luciferase reporter assay confirmed that OTX2 directly interacted with the promoter region of p21 to enhance its transcription, and DMBX1 repressed OTX2-mediated transcription of p21. Our study reveals that DMBX1 plays an oncogenic role in LUAD by repressing OTX2-mediated transcription of p21 and the results may provide new therapeutic targets for LUAD patients.

A clinical, biologic and mechanistic analysis of the role of ZNF692 in cervical cancer.

OBJECTIVE: Cervical cancer (CC) is the most common malignancy in women. The zinc finger protein 692 (ZNF692) has been identified as a transcription factor and its aberrant expression participates in tumorigenesis of various cancers. However, its biological function and molecular mechanisms in cervical cancer remain unclear. METHODS: Microarrays were analysed by immunohistochemistry (IHC) to investigate the expression of ZNF692 in cervical cancer and its relationship with clinicopathologic characteristics. siRNAs and expression plasmids were used to reveal the biological function of ZNF692 in CC and subcutaneous xenograft model to examine the role of ZNF692 in vivo. Chromatin Immunoprecipitation and luciferase reporter assay were performed to ascertain whether ZNF692 binds to the promoter region of p27kip1. RESULTS: By analyzing The Cancer Genome Atlas (TCGA) dataset, we confirmed ZNF692 as a potential oncogene in CC. ZNF692 expression was up-regulated in CC tissues compared with that in adjacent normal tissues, and its overexpression was correlated with poor clinicopathologic characteristics. Moreover, ZNF692 promoted the proliferation, migration and invasion of CC cells both in vitro and in vivo. Regarding molecular mechanisms, up-regulation of ZNF692 was found to enhance the G1/S transition via regulating the p27kip1/PThr160-CDK2 signal pathway in CC cells. CONCLUSION: ZNF692 promotes CC cells proliferation and invasion through suppressing p27kip1 transcription by directly binding its promoter region, which suggests that ZNF692 may serve as an underlying therapeutic target and prognostic marker in CC.

LncRNA DUXAP10 modulates cell proliferation in esophageal squamous cell carcinoma through epigenetically silencing p21.

Esophageal Squamous Cell Carcinoma (ESCC) belongs to malignant tumor of human digestive system. It has greatly threatened human health both mentally and physically. Long non-coding RNAs have been discovered to be special molecular regulators in various cancers, including ESCC. LncRNA DUXAP10 is a newfound RNA, which is able to improve the progression of cancers 1-3 . In this study, DUXAP10 was certified to be upregulated in ESCC tissues and cells. Besides, it was positively correlated with short survival time. Moreover, down-expression of DUXAP10 contributed to decreased cell proliferation and metastasis. Silenced DUXAP10 led to increased apoptosis rate and stagnation of cell cycle. Results of mechanism experiments suggested that DUXAP10 motivated ESCC progression through recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p21. Our findings suggested that the pseudogene-derived from lncRNA DUXAP10 drove the biological progression of ESCC. DUXAP10 was likely to be a potential therapeutic target for ESCC.

SNAP23 suppresses cervical cancer progression via modulating the cell cycle.

OBJECTIVE: Cervical cancer (CC) is one of the most common gynecologic tumors in women worldwide, with poor prognosis and low survival rate. In this study, we identified SNAP23 as a potential tumor suppressor gene in CC. METHODS: The expression of SNAP23 in tissues and cell lines were measured by qRT-PCR, western blot and IHC. Knockdown of SNAP23 by siRNA and ectopic expression of SNAP23 by overexpression plasmid were performed to observe the biological function of SNAP23 in CC. Xenograft nude mice models were established to measure its function in vivo. RESULTS: SNAP23 was downregulated in CC tissues and had a negative correlation with advanced clinical characteristics. Ectopic expression of SNAP23 suppressed malignant phonotype of CC while knockdown of SNAP23 promoted the progression of CC in vitro. The flow cytometry analysis revealed that SNAP23 exerted its tumor suppressor activity via inducing G2/M cell cycle arrest. Moreover, xenograft tumor models showed that SNAP23 suppresses tumor growth in vivo. CONCLUSIONS: Our results revealed that SNAP23 suppressed progression of CC and induced cell cycle G2/M arrest via upregulating p21cip1 and downregulating CyclinB1.

HOXC13 promotes proliferation of esophageal squamous cell carcinoma via repressing transcription of CASP3.

Esophageal squamous cell carcinoma (ESCC), the dominant subtype of esophageal cancer, is one of the most common digestive tumors worldwide. In this study, we confirmed that HOXC13, a member of the homeobox HOXC gene family, was significantly upregulated in ESCC and its overexpression was associated with poorer clinical characteristics and worse prognosis. Moreover, knockdown of HOXC13 inhibited proliferation and induced apoptosis of ESCC through upregulating CASP3. ChIP analysis revealed that HOXC13 repressed transcription of CASP3 through directly targeting the promotor region of CASP3. We also found that miR-503 downregulated HOXC13, by directly targeting its 3'UTR, and inhibited proliferation of ESCC. In conclusion, our study demonstrates that HOXC13, which is directly targeted by miR-503, promotes proliferation and inhibits apoptosis of ESCC through repressing transcription of CASP3.

MUC1 overexpression predicts worse survival in patients with non-small cell lung cancer: evidence from an updated meta-analysis.

BACKGROUND: Previous studies on the prognostic role of MUC1 expression in non-small cell lung cancer (NSCLC) remain controversial. We conducted a meta-analysis to appraise the clinicopathological and prognostic effect of MUC1 in NSCLC patients. MATERIALS AND METHODS: Searches of PubMed, EMBASE and CNKI (Chinese National Knowledge Infrastructure) were conducted and relevant studies were extracted. The pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence intervals (CIs) were used to estimate effects. Heterogeneity among studies and publication bias were also evaluated. RESULTS: A total of 15 studies with 1,682 patients were included in this meta-analysis. The pooled HRs indicated that elevated MUC1 expression was associated with poorer overall survival (HR = 2.12, 95% CI: 1.47-3.05; P < 0.001) and progression-free survival (HR = 2.00, 95% CI: 1.53-2.62; P < 0.001) in patients with NSCLC. Significant associations were also found in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (HR = 3.16, 95% CI: 2.21-4.52, P < 0.001) and with a platinum-based regimen (HR = 4.35, 95% CI: 2.45-7.72, P < 0.001). Additionally, MUC1 overexpression was significantly associated with performance status (OR = 2.32, 95% CI: 1.13-4.73, P = 0.021). CONCLUSIONS: MUC1 could be a valuable biomarker of the prognoses of NSCLC patients.