Treatment for T1 colorectal cancers substratified by site and size: "horses for courses".

Background: Owing to advances in diagnostic technology, the diagnosis of T1 colorectal cancers (CRCs) continues to increase. However, the optimal management of T1 CRCs in the Western Hemisphere remains unclear due to limited population-based data directly comparing the efficacy of endoscopic therapy (ET) and surgical resection (SR). The purpose of this study was to report outcome data from a large Western cohort of patients who underwent ET or SR for early CRCs. Methods: The SEER-18 database was used to identify patients with T1 CRCs diagnosed from 2004 to 2018 treated with ET or SR. Multivariable logistic regression models were employed to identify variables related to lymph node metastasis (LNM). Rates of ET and 1-year relative survival were calculated for each year. Effect of ET or SR on overall survival and cancer-specific survival was compared using Kaplan-Meier method stratified by tumor size and site. Results: A total of 28,430 T1 CRCs patients were identified from 2004 to 2018 in US, with 22.7% undergoing ET and 77.3% undergoing SR. The incidence of T1 CRCs was 6.15 per 100,000 person-years, with male patients having a higher incidence. Left-sided colon was the most frequent location of tumors. The utilization of ET increased significantly from 2004 to 2018, with no significant change in 1-year relative survival rate. Predictors of LNM were age at diagnosis, sex, race, tumor size, histology, grade, and location. The 5-year relative survival rates were 91.4 and 95.4% for ET and SR, respectively. Subgroup analysis showed that OS and CSS were similar between ET and SR in T1N0M0 left-sided colon cancers with tumors 2 cm or less and in rectal cancers with tumors 1 cm or less. Conclusion: Our study showed that ET was feasible and safe for patients with left-sided T1N0M0 colon cancers and tumors of 2 cm or less, as well as T1N0M0 rectal cancers and tumors of 1 cm or less. Therefore, the over- and under-use of ET should be avoided by carefully selecting patients based on tumor size and site.

Time Trend Analysis of Splenectomy for Splenic Marginal Zone Lymphoma: Declining Surgery, Promising Survival.

BACKGROUND: The purpose of current study was to examine the incidence, characteristics, treatment, and survival of splenic marginal zone lymphoma (SMZL). METHODS: Using SEER-18 database, patients diagnosed with SMZL between 2000 and 2018 were included. Effect of splenectomy on survival was evaluated after balancing the confounding factors by propensity score matching. Rates of splenectomy and 1-year relative survival were calculated for each year. A logistic regression model identified factors related to splenectomy, and a Cox regression model assessed factors linked to overall survival (OS). RESULTS: A total of 2790 patients with SMZL were analyzed. The majority were older than 60 years, female, and white. The age-adjusted incidence of SMZL was 0.17/100,000 person-years, with higher incidence in males. Incidence increased by 0.68%/year and peaked at 80-84 years for both genders. The SMZL-specific survival rates at 3 and 5 years were 89.6% and 85.3%, respectively. Meanwhile, the relative survival rates for the same periods were 88.6% and 85.9%, respectively. Splenectomy patients were more likely to be younger, male, and diagnosed with early-stage disease. Despite the decreasing utilization rate of splenectomy from 59.4% in 2000 to 16.2% in 2018, the 1-year relative survival rate remained relatively stable with minor fluctuations over time. Whether or not the patient underwent splenectomy was not found to be a significant prognostic indicator for OS. CONCLUSIONS: Our study demonstrated a decreasing use of splenectomy but a relatively stable survival in patients with SMZL, highlighting the urgency to better understand the role of splenectomy and its associated outcomes.

Causes of death among patients with hepatocellular carcinoma in United States from 2000 to 2018.

BACKGROUND: The gains in survival outcomes of US patients with hepatocellular carcinoma (HCC) have come at the expense of developing non-cancer-related morbidities, such as cardiovascular diseases (CVDs) and infections. However, population-based data on causes of death (CODs) in patients with HCC are scarce. METHODS: A cancer registry database in the United States was used to analyze the CODs among patients with HCC. Death cause distribution and standardized mortality ratios were calculated to quantify the disease-specific death burden. RESULTS: A total of 40,094 patients with a histological diagnosis of HCC were identified from the SEER-18 database between 2000 and 2018, of which 30,796 (76.8%) died during the follow-up period. The majority of these deaths (25,153, 81.7%) occurred within 2 years after diagnosis, 13.2% (4075) occurred within 2-5 years, and 5.1% (1568) occurred after 5 years. All age groups had a lower burden of female deaths than of male deaths during the study period. With respect to CODs, 23,824 (77.4%), 2289 (7.4%), and 4683 (15.2%) were due to HCC, other cancers, and non-cancer causes, respectively. Non-cancer-related deaths were more common among older patients and those with longer latency periods since diagnosis. The major causes of non-cancer-related deaths are other infectious and parasitic diseases, including HIV and CVDs. CONCLUSIONS: CODs during HCC survivorship varied, and a growing number of survivors tended to die from causes other than HCC, with an increasing latency period since diagnosis. Comprehensive analyses of mortality patterns and temporal trends could underpin strategies to reduce these risks.

Risk of second primary malignancies in survivors of pancreatic neuroendocrine neoplasms from 2000 to 2018.

BACKGROUND AND AIM: As a result of improved survival, cancer survivors continue to remain at risk of developing second primary malignancies (SPMs). However, the association between first primary pancreatic neuroendocrine neoplasms (PanNENs) and SPMs has not been thoroughly investigated. METHODS: Using the Surveillance, Epidemiology, and End Results-18 database, patients histologically diagnosed with PanNENs as their first malignancy between 2000 and 2018 were identified. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) and excess absolute risks per 10 000 person-years of SPMs were calculated to estimate the risk of being diagnosed with subsequent cancers compared with the general population. RESULTS: A total of 489 (5.7%) PanNENs survivors developed an SPM during the follow up, with a median latency between first and second cancer diagnoses of 32.0 months. The overall SIR of SPMs was 1.30 (95% CI: 1.19, 1.42) and the excess absolute risk was 35.67 cases per 10 000 person-years in comparison with the general population. Age 25-64 years at PanNENs diagnosis was associated with statistically higher risks for SPMs of all cancers combined. Latency stratification was significant for elevated SPMs risk between 2-23 and 84+ months after diagnosis. White patients were found to have a significantly increased incidence of SPMs (SIR: 1.23, 95% CI: 1.11, 1.35), mainly owing to the higher risk of stomach, small intestine, pancreas, kidney and renal pelvis, and thyroid cancers. CONCLUSION: Pancreatic neuroendocrine neoplasms survivors experience a significant increase in the burden of SPMs compared with the reference population. The heightened relative risk calls for careful long-term scrutiny as part of survivorship care plans.

Early-onset pancreatic neuroendocrine neoplasms: A distinct disease with improved survival compared with old individuals.

Background: The incidence, clinicopathologic characteristics, treatment patterns, and survival of early-onset pancreatic neuroendocrine neoplasms (EOPanNENs) have not been well explored. Methods: Patients diagnosed with PanNENs were identified from the SEER database between 2000 and 2018. EOPanNENs were defined as diagnosis in patients aged less than 50 years, while the remaining were defined as later-onset pancreatic neuroendocrine neoplasms (LOPanNENs). Incidence, clinical features, management, and prognosis were analyzed in our study. Multivariable analyses were performed to identify factors associated with overall survival (OS) in EOPanNENs and LOPanNENs, respectively. Results: A total of 5172 patients with PanNENs were included: 1267 (24.5%) in the EOPanNENs cohort and 3905 (75.5%) in the LOPanNENs cohort. The age-adjusted incidence rate significantly increased among later-onset cases, while it remained relatively stable in early-onset cases. EOPanNENs were more frequently to be female, unmarried, and with better tumor differentiation compared with LOPanNENs. Of note, early-onset patients presented with a higher rate of lymph node involvement, and they were more likely to receive surgical treatment. For local-regional disease at presentation, surgery alone was the most frequently used regimen over the last two decades. With regard to distant stage, a combination of surgery and chemotherapy was more often utilized. Risk factors for PanNENs survival were more correlated with LOPanNENs compared with EOPanNENs. The OS and cancer-specific survival (CSS) were significantly better in the EOPanNENs group. Further analyses showed that EOPanNENs ≤ 2cm were associated with more favorable survival outcomes than EOPanNENs>2cm. Conclusion: EOPanNENs are a clinically rare and distinct entity from LOPanNENs. The advantages in survival for the EOPanNENs cohort over time were largely driven by the indolent clinical courses including better tumor differentiation and intensified surgical treatment. Further investigations are warranted to better understand the characteristics of this disease subgroup.

Targeting uridine-cytidine kinase 2 induced cell cycle arrest through dual mechanism and could improve the immune response of hepatocellular carcinoma.

BACKGROUND: Pyrimidine metabolism is critical for tumour progression. Uridine-cytidine kinase 2 (UCK2), a key regulator of pyrimidine metabolism, is elevated during hepatocellular carcinoma (HCC) development and exhibits carcinogenic effects. However, the key mechanism of UCK2 promoting HCC and the therapeutic value of UCK2 are still undefined. The aim of this study is to investigate the potential of UCK2 as a therapeutic target for HCC. METHODS: Gene expression matrices were obtained from public databases. RNA-seq, co-immunoprecipitation and RNA-binding protein immunoprecipitation were used to determine the mechanism of UCK2 promoting HCC. Immune cell infiltration level and immune-related functional scores were evaluated to assess the link between tumour microenvironment and UCK2. RESULTS: In HCC, the expression of UCK2 was upregulated in part by TGFß1 stimulation. UCK2 promoted cell cycle progression of HCC by preventing the degradation of mTOR protein and maintaining the stability of PDPK1 mRNA. We also identified UCK2 as a novel RNA-binding protein. Downregulation of UCK2 induced cell cycle arrest and activated the TNFα/NFκB signalling pathway-related senescence-associated secretory phenotype to modify the tumour microenvironment. Additionally, UCK2 was a biomarker of the immunosuppressive microenvironment. Downregulated UCK2 induced a secretory phenotype, which could improve the microenvironment, and decreased UCK2 remodelling metabolism could lower the resistance of tumour cells to T-cell-mediated killing. CONCLUSIONS: Targeting UCK2 inhibits HCC progression and could improve the response to immunotherapy in patients with HCC. Our study suggests that UCK2 could be an ideal target for HCC.

RPNs Levels Are Prognostic and Diagnostic Markers for Hepatocellular Carcinoma.

The ribophorin family (RPN) is an essential regulatory subunit of the proteasome. By influencing the ubiquitin-proteasome system activity, ribophorins (RPNs) are responsible for almost all physiology and pathology processes of mammalian cells. Nevertheless, little is known about the role of RPNs in HCC. In this work, we first evaluated the transcriptional levels and the prognostic and diagnostic value of RPNs based on the public database. Firstly, we found all RPNs were surprisingly consistently upregulated in HCC tissues. Moreover, the RPNs' expression pattern is correlated with HCC tumor grade. The TCGA HCC platforms' data indicated that RPN2, RPN3, RPN6, RPN9, RPN10, RPN11, and RPN12 have robust diagnosis values. Then, survival analysis revealed that the high expression of RPN1, RPN2, RPN4, RPN5, RPN6, RPN9, and RPN11 was correlated with unfavourable HCC overall survival. Then, genetic alteration, immune infiltration feature, gene-genes network, and functional enrichment for RPNs indicated that RPNs have many potential biosynthesis activities expert for UPS functions. Moreover, western blot and qRT-PCR results confirmed these results. The silencing of RPN6 and RPN9 significantly reduced HCC cells' proliferation, migration, and invasion ability in vitro. An in vivo tumor model further validated the oncogene effect of RPN6 on HCC cell growth. Moreover, RPN6 and RPN9 could promote cell migratory and invasive potential by affecting the epithelial-mesenchymal transition (EMT) process. In summary, this study suggests that the RPN family has the potential to be potential biomarkers and targets for HCC.

Survival Benefit of Surgical Resection for Pancreatic Neuroendocrine Tumors With Oligometastatic Liver Metastasis: A Retrospective and Propensity Score-Matching Analysis.

Background: Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of pancreatic malignancies. Surgical resection is the only curative treatment option for patients with localized PanNETs, yet the role of cancer-directed surgery (CDS) in the setting of oligometastatic liver metastasis remains a controversy. Methods: All patients diagnosed with PanNETs and liver-only metastasis from 2010 to 2018 were identified from the SEER database. The biases of baseline characteristics between CDS and no-CDS cohorts were reduced by the propensity score-matching (PSM) method, and the prognostic role of CDS was estimated using the Kaplan-Meier method and Cox regression models. Logistic regression analysis was utilized to identify factors associated with patients who underwent CDS. Results: A total of 1,270 PanNET patients with oligometastatic liver metastasis were included and analyzed. Of these patients, 283 (22.3%) patients underwent CDS of the primary tumor, while the remaining 987 (77.7%) did not. The OS and CSS were significantly better in the CDS cohort regardless of the propensity score analysis. Multivariate analysis revealed that age, tumor differentiation, tumor location, and lymph node status were significantly associated with patients who were more likely to receive CDS. Conclusion: Our study demonstrated that CDS was associated with survival benefits in selected patients with PanNETs and liver-only metastasis based on a large population database.

A Circular RNA, Cholangiocarcinoma-Associated Circular RNA 1, Contributes to Cholangiocarcinoma Progression, Induces Angiogenesis, and Disrupts Vascular Endothelial Barriers.

BACKGROUND AND AIMS: Circular RNAs (circRNAs) and extracellular vesicles (EVs) are involved in various malignancies. We aimed to clarify the functions and mechanisms of dysregulated circRNAs in the cells and EVs of cholangiocarcinoma (CCA). APPROACH AND RESULTS: CircRNA microarray was used to identify circRNA expression profiles in CCA tissues and bile-derived EVs (BEVs). CCA-associated circRNA 1 (circ-CCAC1) expression was measured by quantitative real-time PCR. The clinical importance of circ-CCAC1 was analyzed by receiver operating characteristic curves, Fisher's exact test, Kaplan-Meier plots, and Cox regression model. The functions of circ-CCAC1 and exosomal circ-CCAC1 were explored in CCA cells and human umbilical vein endothelial cells (HUVECs), respectively. Different animal models were used to verify the in vitro results. RNA sequencing, bioinformatics, RNA immunoprecipitation, RNA pulldown, chromatin immunoprecipitation followed by sequencing, and luciferase reporter assays were used to determine the regulatory networks of circ-CCAC1 in CCA cells and HUVECs. Circ-CCAC1 levels were increased in cancerous bile-resident EVs and tissues. The diagnostic and prognostic values of circ-CCAC1 were identified in patients with CCA. For CCA cells, circ-CCAC1 increased cell progression by sponging miR-514a-5p to up-regulate Yin Yang 1 (YY1). Meanwhile, YY1 directly bound to the promoter of calcium modulating ligand to activate its transcription. Moreover, circ-CCAC1 from CCA-derived EVs was transferred to endothelial monolayer cells, disrupting endothelial barrier integrity and inducing angiogenesis. Mechanistically, circ-CCAC1 increased cell leakiness by sequestering enhancer of zeste homolog 2 in the cytoplasm, thus elevating SH3 domain-containing GRB2-like protein 2 expression to reduce the levels of intercellular junction proteins. In vivo studies further showed that increased circ-CCAC1 levels in circulating EVs and cells accelerated both CCA tumorigenesis and metastasis. CONCLUSIONS: Circ-CCAC1 plays a vital role in CCA tumorigenesis and metastasis and may be an important biomarker/therapeutic target for CCA.

Deoxyelephantopin induces apoptosis via oxidative stress and enhances gemcitabine sensitivity in vitro and in vivo through targeting the NF-κB signaling pathway in pancreatic cancer.

Pancreatic cancer is a highly invasive malignant tumor of the digestive system with an unfavorable prognosis worldwide. This trait is thought to be largely attributed to chemoresistance. Chemotherapy is the only hope for patients with advanced pancreatic cancer. Therefore, seeking new effective chemotherapy drugs has become an urgent need. The purpose of our study was to explore whether deoxyelephantopin (DET), a sesquiterpene lactone, has a potential antitumor effect in pancreatic cancer. Additionally, the antitumor effects of DET alone or in combination with gemcitabine (GEM) and the potential mechanism of this combination were revealed. In vitro experiments showed that DET suppressed the proliferation, invasion and metastasis of pancreatic cancer cells, induced cell apoptosis via oxidative stress, and enhanced GEM sensitivity by inhibiting the NF-κB signaling pathway. Beyond that, in vivo experiments showed that DET not only inhibited pancreatic tumor growth and metastasis but also amplified the antitumor capacity of GEM, which was related to the downregulation of NF-κB and its downstream gene products. In summary, it is possible that DET could be developed as a single agent or combined with conventional chemotherapy drugs to improve the treatment of pancreatic cancer.

Colorectal cancer-derived exosomal miR-106b-3p promotes metastasis by down-regulating DLC-1 expression.

Cancer-derived exosomal miRNAs play an important role in the development of metastasis, but the effects and underlying mechanisms remain unclear. In the present study, we investigated the miRNA expression profiles of 5 paired serum exosomal samples from metastatic colorectal cancer (mCRC) and non-mCRC patients via RNA sequencing. After we evaluated the differentially expressed miRNAs in 80 CRC patients, miR-106b-3p was selected as a metastasis-associated miRNA of CRC. We showed that the expression level of serum exosomal miR-106b-3p was significantly higher in CRC patients with metastasis than those without metastasis. Additionally, high serum exosomal miR-106b-3p expression in patients was correlated with a poor prognosis. Coculture of low-metastatic CRC cells with high-metastatic CRC cell-derived exosomes promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), which was caused by the transport and transduction of miR-106b-3p in vitro. Moreover, exosomal miR-106b-3p promoted lung metastasis of CRC cells in vivo. In addition, we demonstrated that miR-106b-3p regulated metastasis by targeting deleted in liver cancer-1 (DLC-1). A negative correlation was also identified between miR-106b-3p and DLC-1 expression in human CRC tumour tissues and in mouse lung metastatic lesions. Collectively, our study indicated that metastasis-associated miR-106b-3p from serum exosomes could be used as a potential prognostic biomarker and therapeutic target for CRC patients.

Identification of lapatinib sensitivity-related genes by integrative functional module analysis.

BACKGROUND: Globally, gastric carcinoma (GC) is one of the most commonly encountered malignancies and is the second highest contributor to cancer mortality. Lapatinib is a potent, orally-bioavailable small-molecule inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases, and is administered to treat GC. However, a large proportion of patients either develop resistance to or do not respond to lapatinib, often because the treatment activates alternative signaling pathways. It is, therefore, vital to identify the key pathways which mediate resistance to lapatinib treatment. METHODS: The lapatinib sensitivity-related genes were extracted from the CellMiner database (version 2.2) using "NCI-60 Analysis Tools". The differentially expressed genes (DEGs) in gastric cancer were derived from The Cancer Genome Atlas (TCGA) database, the protein-protein interaction (PPI) network was derived from the Human Protein Reference Database (HPRD), and the Database for Annotation, Visualization and Integrated Discovery (DAVID) facilitated the functional analysis. The cell function was tested by CCK-8 cell viability assay, colony formation assay, acridine orange/ethidium bromide (AO/EB) staining, and Transwell assay. RESULTS: The functional linkage networks of lapatinib sensitivity were constructed. Two modules were identified, and pathway analysis indicated that these modules were involved in several pathways, including the neuroactive ligand-receptor interaction network and the Rap1 signaling pathway. Finally, the breast cancer anti-estrogen resistance 1 (BCAR1) gene was selected for further study with lapatinib-resistant SUN216 cells (SUN216/LR). We found the expression of BCAR1 was upregulated in SUN216/LR cells compared to SUN216 cells. The IC50 of lapatinib in SUN216/LR cells was reduced upon BCAR1 knockdown, as measured by a CCK-8 assay. A clonogenic assay showed fewer SUN216/LR colonies with BCAR1 knockdown and lapatinib treatment. CONCLUSIONS: In brief, we efficiently identified those crucial modules highly related to lapatinib sensitivity in GC by using a topological network method. BCAR1 was identified as a potentially critical gene that plays a role in lapatinib sensitivity, and experiments confirmed that BCAR1 might contribute to lapatinib resistance in GC. These results provide further insight into the molecular basis of lapatinib sensitivity and may offer novel strategies for the future treatment of GC.

Up-regulated LINC00261 predicts a poor prognosis and promotes a metastasis by EMT process in cholangiocarcinoma.

OBJECTIVE: LINC00261 plays a vital role in tumorigenesis and metastasis of digestive system cancer. However, an influence of LINC00261 on cholangiocarcinoma has a little research. There, we investigated clinical role and molecular mechanisms of LINC00261 in cholangiocarcinoma. METHODS: The qRT-PCR was performed for the detection of LINC00261 level in 50 paired specimens from CCA patients and six cell lines. Cell proliferation were explored by CCK-8 and colony formation assays in QBC939 and RBE cells after transfected with si-LINC00261 or si-NC. Then, AO/EB double fluorescence staining and flow cytometric assays were performed to assess cell apoptosis. Transwell and wound healing assays were selected to evaluate migratory and invasive property of cells. Protein levels, such as PCNA, Bax, Bcl-2, and several epithelial-to-mesenchymal transition markers, including E-cadherin, N-cadherin and Vimentin, were detected by western blot assays. Furthermore, we use a R2 platform to evaluate the correlation between LINC00261 and EMT makers and predict the overall survival and relapse-free survival for CCA patients by the expression of LINC00261/ EMT makers. RESULTS: LINC00261 was overexpressed in cancerous tissues and CCA cell lines compared with adjacent tissues and HIBEC, respectively. Up-regulation of LINC00261 was related to larger tumor size (p = 0.009), positive lymph node metastasis (p = 0.021), advanced TNM stages (p = 0.017) and higher postoperative recurrence (p = 0.009) for CCA patients. Additionally, univariate and multivariate analysis displayed that LINC00261 an independent prognostic factor in CCA patients. Knockdown of LINC00261 expression in RBE and QBC939 cell lines inhibited cell proliferation, migration and invasion property and increased cell apoptosis and the EMT progression. Moreover, there was a strong correlation between LINC00261 and E-cadherin (CDH1) (p < 0.05), and low expression of E-cadherin (CDH1) has a poor overall survival and relapse-free survival in CCA patients (p < 0.05). CONCLUSION: Overall, high level of LINC00261 in CCA predicts a poor prognosis, and promotes a metastasis via EMT process. Thus, LINC00261 could be a promising biomarker and therapeutic target for CCA, and in the high level of LINC00261 in CCA, E-cadherin or CDH1 might be an effective factor for tumor metastasis or poor prognosis.

Up-regulation of ZFAS1 indicates dismal prognosis for cholangiocarcinoma and promotes proliferation and metastasis by modulating USF1 via miR-296-5p.

LncRNAs has been demonstrated to modulate neoplastic development by modulating downstream miRNAs and functional genes. In this study, we aimed to detect the interaction among lncRNA ZFAS1 miR-296-5p and USF1. We explored the proliferation, migration and invasion of cholangiocarcinoma. The differentially expressed ZFAS1 was discovered in both tissues and cell lines by qRT-PCR. The targeting relationship between miR-296-5p and ZFAS1 or USF1 was validated by dual-luciferase assay. The impact of ZFAS1 on CCA cell proliferation was observed by CCK-8 assay. The protein expression of USF1 was determined by Western blot. The effects of ZFAS1, miR-296-5p and USF1 on tumour growth were further confirmed using xenograft model. LncRNA ZFAS1 expression was relatively up-regulated in tumour tissues and cells while miR-296-5p was significantly down-regulated. Knockdown of ZFAS1 significantly suppressed tumour proliferation, migration, invasion and USF1 expression. Overexpressed miR-296-5p suppressed cell proliferation and metastasis. Knockdown of USF1 inhibited cell proliferation and metastasis and xenograft tumour growth. In conclusion, ZFAS1 might promote cholangiocarcinoma proliferation and metastasis by modulating USF1 via miR-296-5p.

Long non-coding RNA NNT-AS1 functions as an oncogenic gene through modulating miR-485/BCL9 in cholangiocarcinoma.

INTRODUCTION: Growing evidence suggests that long non-coding RNAs (lncRNAs) could function as important regulators in carcinogenesis and cancer progression. Nicotinamide nucleotide transhydrogenase antisense RNA 1 (lncRNA NNT-AS1) is up-regulated in some human tumors and functions as a tumor promoter. This study aimed to detect the effect of NNT-AS1 on cholangiocarcinoma (CCA) prognosis. MATERIALS AND METHODS: In this study, we detected NNT-AS1 expression in CCA tissue samples and cell lines, and analyzed the association between NNT-AS1 expression levels and clinical parameters of CCA patients. Moreover, we conducted loss-of-function studies in CCA cancer cells to explore the biological function and molecular mechanism of NNT-AS1. NNT-AS1 was downregulated by using RNAi technology. Cell proliferation was examined by CCK8 and clone formation assays. Cell migration and invasion were determined by wound healing and transwell assays. Western blot assays were used to explore protein expression. RESULTS: In this study, NNT-AS1 was expressed at high levels in CCA and closely associated with poor prognosis of patients with CCA. NNT-AS1 knockdown impaired cell proliferation, suppressed CCA cell migration and invasion, and restrained tumor growth in vitro. Moreover, NNT-AS1 directly bounded to miR-485 and further regulated BCL9. Finally, rescue assays verified that NNT-AS1 modulated the tumorigenesis of CCA by regulating miR-485. CONCLUSION: Taken together, NNT-AS1 played a critical biological role in the development of CCA. Our results elucidated NNT-AS1/miR-485/BCL9 axis might lead to a further understanding of the molecular mechanism of CCA.

Akirin2 is modulated by miR-490-3p and facilitates angiogenesis in cholangiocarcinoma through the IL-6/STAT3/VEGFA signaling pathway.

Akirin2 is a key regulator of embryonic development and the innate immunity response. However, this regulator's role in tumorigenesis especially in cholangiocarcinoma (CCA) development has not been thoroughly elucidated to date. In the current work, we used RT-qPCR, western blot analysis, and immunohistochemistry (IHC) to explore the expression level of Akirin2, and the relationship between Akirin2 levels and clinicopathological characteristics was evaluated. The biological functions of Akirin2 were examined in vitro and in vivo by using a lentiviral vector system. Luciferase reporter assays were applied to detect the direct binding relationship between the 3'-UTR of Akirin2 mRNA and miR-490-3p. The results showed that Akirin2 was overexpressed in CCA and this upregulation was associated with a shorter overall survival. Silencing or overexpressing Akirin2 by lentiviral approaches significantly influenced CCA cell proliferation, migration, invasion, and angiogenesis. An in vivo tumor model further validated the oncogenic effect of Akirin2 on CCA cell growth, metastasis, and angiogenesis. Mechanistic studies demonstrated that Akirin2 induced angiogenesis by increasing the expression of VEGFA by activating the IL-6/STAT3 signaling pathway. Akirin2 promoted cell migratory and invasive potential by affecting the epithelial-mesenchymal transition (EMT) process. In addition, Akirin2 expression was negatively controlled by miR-490-3p in CCA cells, and miR-490-3p attenuated cell migration and angiogenesis in CCA cells by silencing Akirin2. Taken together, the data indicated that Akirin2 could be regulated by miR-490-3p at the posttranscriptional level and facilitate CCA cell progression via the IL-6/STAT3/VEGFA signaling pathway. The present study may expedite the development of novel therapeutic strategies for CCA.

Radical modular pancreatoduodenectomy for pancreatic head cancer using a combination of multiple artery-first approaches technique.

The aim of this study was to describe and assess the efficacy of a combination of multiple artery-first approaches (CMAFA) in pancreatoduodenectomy (PD) depending on the tumor location from an embryonic point of view.Between January 2011 and December 2016, seventy-nine consecutive patients with pancreatic head cancer (PHC) underwent PD with curative intent. Patients were classified into two groups according to the surgical procedure: CMAFA-PD group (n = 38) and conventional PD (Co-PD) group (n = 41). Clinicopathlogical variables and clinical outcomes were compared among the two groups.The CMAFA technique demonstrated an improved rate of R0 resection (89.5% vs. 70.7%, P = .038) and a higher median lymph node yield (24 vs.20, P = .034). The CMAFA-PD group was associated with reduced blood loss (450 vs. 600 ml, P = .049), lower rate of blood transfusion (23.7% vs. 46.3%, P = .035), and shorter length of hospital stay (19 vs. 26 days, P < .001). The rates of 90-day mortality, major morbidity, and readmission were comparable among the two groups.This study demonstrates that CMAFA is a feasible and efficient technique with acceptable perioperative and oncological outcomes in treating patients with PHC.

Increased Expression of Circular RNA circ_0005230 Indicates Dismal Prognosis in Breast Cancer and Regulates Cell Proliferation and Invasion via miR-618/ CBX8 Signal Pathway.

BACKGROUND/AIMS: Circular RNAs (circRNAs) are a class of non-coding RNAs. They have been proved to be critically involved in tumorigenesis and progression of malignancies through competing endogenous RNA (ceRNA) mechanism. Nevertheless, the exploration between circRNAs and pathogenesis of breast cancer (BC) is limited. Previously, circ_0005230 was identified upregulated in BC tissues screened by circRNA microarray. In the present study, we aimed to investigate the expression pattern, functional role, and mechanism of circ_0005230 in BC. METHODS: qRT-PCR was conducted to elucidate the expression levels of circ_0005230 in BC tissues and cells. Additionally, the clinical severity and prognostic value were investigated. CCK-8, colony-forming, flow cytometric assays were performed. Animal study was conducted to validate the in vitro data. What's more, Transwell assays were induced to detect the cell metastatic properties of circ_0005230 exerts in BC cells. Luciferase reporter assay was used to measure the mechanism of circ_0005230. RESULTS: circ_0005230 was overexpressed in BC tissue specimens and cell lines. The overexpression of circ_0005230 was related to adverse phenotypes in the patients with BC. In addition, circ_0005230 could be regarded as a prognostic predictor in BC patients. In vitro and in vivo data demonstrated the cell growth promoting role of circ_0005230. Moreover, circ_0005230 could also promote cell migratory and invasive capacities. For the mechanism investigation, circ_0005230 was proved to be a sponge of miR-618, and expression of miR-618 could regulate CBX8 expression via targeting the 3'UTR of CBX8. Rescue assays also illustrated an oncogenic function of circ_0005230 in BC via acting as a miR-618 sponge to promote CBX8 expression. CONCLUSION: circ_0005230/miR-618/CBX8 axis might play a key role in BC tumorigenesis and development.