Diagnosis and management of urinary bladder paragangliomas: A Sino-American-European retrospective observational study.

OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice.

Purpose: Alcohol consumption increases the risk of breast cancer and promotes cancer progression. Alcohol exposure could affect both processes of the mammary carcinogenesis, namely, the cell transformation and onset of tumorigenesis as well as cancer aggressiveness including metastasis and drug resistance/recurrence. However, the cellular and molecular mechanisms underlying alcohol tumor promotion remain unclear. There are four members of the mammalian p38 mitogen-activated protein kinase (MAPK) family, namely, p38α, p38ß, p38γ and p38δ. We have previously demonstrated alcohol exposure selectively activated p38γ MAPK in breast cancer cells in vitro and in vivo. Pirfenidone (PFD), an antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis, is also a pharmacological inhibitor of p38γ MAPK. This study aimed to determine whether PFD is useful to inhibit alcohol-induced promotion of breast cancer. Methods: Female adolescent (5 weeks) MMTV-Wnt1 mice were exposed to alcohol with a liquid diet containing 6.7% ethanol. Some mice received intraperitoneal (IP) injection of PFD (100 mg/kg) every other day. After that, the effects of alcohol and PFD on mammary tumorigenesis and metastasis were examined. Results: Alcohol promoted the progression of mammary tumors in adolescent MMTV-Wnt1 mice. Treatment of PFD blocked tumor growth and alcohol-promoted metastasis. It also significantly inhibited alcohol-induced tumorsphere formation and cancer stem cell (CSC) population. Conclusion: PFD inhibited mammary tumor growth and alcohol-promoted metastasis. Since PFD is an FDA-approved drug, the current findings may be helpful to re-purpose its application in treating aggressive breast cancer and alcohol-promoted mammary tumor progression.

Analysis of current situation and influencing factors of marital adjustment in patients with Crohn's disease and their spouses.

The purpose of this study was to investigate the marital adjustment of patients with Crohn's disease and their spouses, and to analyze its influencing factors. It lays the investigation foundation for the follow-up binary study of Crohn's disease patients and their spouses. Using convenience sampling, 177 pairs of patients and their spouses from a tertiary hospital in Nanjing, China were selected. With face-to-face electronic questionnaires to survey the patient and spouse, the contents include the Lock-Wollance Marriage Adjustment Test, Subjective Well-Being Scale for Chinese Citizens, Couple Support Questionnaire, and Distress Self-Disclosure Scale. The marital adjustment score of patients was (99.03 ±â€…24.25), and the marital adjustment score of spouses was (99.61 ±â€…25.39). The proportions of patients with marital disorders and their spouses with marital disorders were 52.5% and 46.9%, respectively. Multiple linear regression showed that the spouse's age, family monthly income, time of diagnosis of Crohn's, distress self-disclosure, marital support, and subjective well-being were important factors influencing the marital adjustment of patients. Self-disclosure of spousal distress, marital support, age, and subjective well-being were important factors that influenced spouses' marital adjustment. Most couples with Crohn's disease have marital disorders, and their marital adjustment affects each other. However, the assessment results of one partner should not be limited to replacing those of the couple. In clinical practice, patient age, monthly family income, self-disclosure of distress, marital support, and subjective well-being should be considered. Spouses should be encouraged to participate in patient care and patient-spouse interventions should be implemented as a whole to improve marital stability.

LncRNA NEAT1 suppresses cellular senescence in hepatocellular carcinoma via KIF11-dependent repression of CDKN2A.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Therapeutic options for advanced HCC are limited, which is due to a lack of full understanding of pathogenesis. Cellular senescence is a state of cell cycle arrest, which plays important roles in the pathogenesis of HCC. Mechanisms underlying hepatocellular senescence are not fully understood. LncRNA NEAT1 acts as an oncogene and contributes to the development of HCC. Whether NEAT1 modulates hepatocellular senescence in HCC is unknown. METHODS: The role of NEAT1 and KIF11 in cellular senescence and tumor growth in HCC was assessed both in vitro and in vivo. RNA pulldown, mass spectrometry, Chromatin immunoprecipitation (ChIP), luciferase reporter assays, RNA FISH and immunofluorescence (IF) staining were used to explore the detailed molecular mechanism of NEAT1 and KIF11 in cellular senescence of HCC. RESULTS: We found that NEAT1 was upregulated in tumor tissues and hepatoma cells, which negatively correlated with a senescence biomarker CDKN2A encoding p16INK4a and p14ARF proteins. NEAT1 was reduced in senescent hepatoma cells induced by doxorubicin (DOXO) or serum starvation. Furthermore, NEAT1 deficiency caused senescence in cultured hepatoma cells, and protected against the progression of HCC in a mouse model. During senescence, NEAT1 translocated into cytosol and interacted with a motor protein KIF11, resulting in KIF11 protein degradation and subsequent increased expression of CDKN2A in cultured hepatoma cells. Furthermore, KIF11 knockdown caused senescence in cultured hepatoma cells. Genetic deletion of Kif11 in hepatocytes inhibited the development of HCC in a mouse model. CONCLUSIONS: Conclusively, NEAT1 overexpression reduces senescence and promotes tumor progression in HCC tissues and hepatoma cells, whereas NEAT1 deficiency causes senescence and inhibits tumor progression in HCC. This is associated with KIF11-dependent repression of CDKN2A. These findings lay the foundation to develop potential therapies for HCC by inhibiting NEAT1 and KIF11 or inducing senescence.

Nomogram for predicting hemodynamic instability and the association between preoperative 3D printing and hemodynamic instability during laparoscopic adrenalectomy for pheochromocytoma.

Laparoscopic adrenalectomy (LA) for resection of pheochromocytomas (PCCs) is associated with high risk of complications and morbidity due to intraoperative hemodynamic instability (HDI). This study aims to identify factors related to HDI during laparoscopic resection of pheochromocytoma and develop a scoring model for prediction of HDI. Data of a total of 119 patients with pathological confirmed PCCs were collected at a single center in China between 2010 and 2021. All patients underwent unilateral LA for PCCs. Clinical and biochemical variables were collected. Next-generation sequencing was performed in all PCCs patients for detection of mutations. Univariate and multivariable logistic regression analyses were used to select risk factors for constructing the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the discrimination of the nomogram. The calibration curve was performed. Finally, four variables including 24 h urinary output of urine vanillylmandelic acid (VMA) ≥ 58 µmol/day, tumor size ≥ 4 cm, right-side tumor location, Cluster 2 mutations were independent risk factors for HDI during LA and were included in the nomogram. The nomogram demonstrated a good discrimination performance with an AUC of 0.784 [95% confidence interval (CI), 0.701-0.867]. The calibration curve showed a bias-corrected AUC of 0.758. Multivariable analysis revealed that preoperative 3D printing is an independent protective factor for HDI. Our study proposed a novel nomogram for prediction of HDI during LA for resection of PCCs. Preoperative 3D printing was associated with HDI in PCCs.

PLAGL1 is associated with prognosis and cell proliferation in pancreatic adenocarcinoma.

BACKGROUND: Emerging evidence has shown the crucial roles of pleomorphic adenoma gene (PLAG) family genes in multiple cancers. However, their functions and mechanisms in pancreatic adenocarcinoma (PAAD) remain poorly understood. METHODS: We analyzed the expression levels of PLAG family genes in both The Cancer Genome Atlas (TCGA) database and a Gene Expression Omnibus (GEO) database, and confirmed the results in our three independent cohorts of 382 PAAD tissues and 362 adjacent nontumor pancreatic tissues. Integrated analyses were carried out to explore the function, mechanism and prognostic value of the selected PLAG family gene in PAAD patients. RESULTS: By analyzing the TCGA and GEO databases, PLAGL1 was identified to be downregulated in PAAD tissues, and its decreasing levels of both mRNA and protein were verified in our three independent PAAD cohorts. PLAGL1 expression was inversely correlated with clinicopathological factors including the Ki67+ cell rate and pathologic stage. Further GSEA of the TCGA-PAAD cohort demonstrated that multiple signaling pathways implicated in cell proliferation were enriched in the lower PLAGL1 expressing PAAD group. Moreover, we demonstrated that PLAGL1 expression was obviously negatively associated with patients' overall survival outcome in both the TCGA-PAAD cohort and our verification cohorts. Additionally, through MTS and BrdU assays, we further demonstrated in vitro that PLAGL1 had the impact of preventing the proliferation of pancreatic cancer cells. CONCLUSIONS: Our present study suggested that downregulated PLAGL1 might act as a biomarker in predicts poor prognosis and one of important factors in increasing cell proliferation in PAAD. This study provides us with a novel prognostic marker and therapeutic strategy for PAAD, which deserves further study.

Adolescent- and adult-initiated alcohol exposure in mice differentially promotes tumorigenesis and metastasis of breast cancer.

BACKGROUND: Alcohol exposure increases the risk of breast cancer. Alcohol consumption by adolescents is a serious social and public health issue. This study investigated the impact of adolescent alcohol consumption on mammary tumorigenesis and progression and compared it to that of adult alcohol exposure in animal models. METHODS: Female adolescent (5 weeks) and adult (8 weeks) MMTV-Wnt1 mice were exposed to alcohol either chronically or acutely. For chronic alcohol exposure, animals were fed a liquid diet containing 6.7% ethanol for 23 weeks. For acute exposure, animals were treated with ethanol (2.5 g/kg, 25% w/v) via intraperitoneal (IP) injection for 15 days. RESULTS: In control animals, the tumor latency was 18.5 to 22 weeks. Both chronic and acute alcohol exposure in adolescent mice significantly shortened the tumor latency to 9.5 and 8.4 weeks, respectively. However, adult-initiated alcohol exposure had little effect on the tumor latency. Both adolescent- and adult-initiated alcohol exposure significantly increased lung metastasis. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased the breast cancer stem cell population. Adolescent-initiated alcohol exposure significantly altered the proliferation of mammary epithelial cells, ductal growth, and the formation of terminal end buds in the mammary glands. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased estradiol levels in the blood. Acute adolescent alcohol exposure also significantly increased blood progesterone levels. Furthermore, adolescent-initiated alcohol exposure activated PAK1 and p38γ MAPK, critical regulators of mammary tumorigenesis and aggressiveness, respectively, while adult-initiated alcohol exposure activated only p38γ MAPK. In addition, both adolescent and adult alcohol exposure significantly decreased the levels of a prognostic marker miR200b. CONCLUSIONS: Adolescent-initiated alcohol exposure enhanced both tumorigenesis and aggressiveness of mammary tumors, while adult-initiated alcohol exposure mainly promoted tumor metastasis. Thus, adolescent mice were more sensitive than adult mice in response to alcohol-induced tumor promotion.

Impact of body composition and genotype on haemodynamics during surgery for pheochromocytoma and paraganglioma.

BACKGROUND: Maintaining intraoperative haemodynamic stability can reduce cardiovascular complications during surgery for pheochromocytoma and paraganglioma (PPGL). Risk factors such as tumour size and catecholamine levels are reported to predict haemodynamic responses during surgery for PPGL. We hypothesized that additional factors including body composition and genetic information could further improve prediction. METHODS: Consecutive patients with PPGL confirmed by surgical pathology between June 2010 and June 2019 were retrospectively included. Cross-sectional computed tomography images at the L3 level were used to assess body composition parameters including skeletal muscle area and visceral fat area. Next-generation sequencing was performed using a panel containing susceptibility genes of PPGL. Differences in clinical-genetic characteristics and body composition parameters were analysed and compared in patients with and without intraoperative haemodynamic instability (HDI). RESULTS: We included 221 patients with PPGL (median age 47 [38-56] years, and 52% male). Among them, 49.8% had Cluster 2 mutations (related to kinase signalling pathways), 44.8% had sarcopenia, and 52.9% experienced intraoperative HDI. Compared with patients without HDI, more patients with HDI had Cluster 2 mutations (59.8% vs. 38.5%, P = 0.002) and less had sarcopenia (35.9% vs. 54.8%, P = 0.005). Multivariate analysis showed that urine vanillylmandelic acid ≥ 58 µmol/day (adjusted odds ratio [OR] = 1.840, 95% confidence interval [CI] = 1.012-3.347, P = 0.046), tumour size ≥ 4 cm (adjusted OR = 2.278, 95% CI = 1.242-4.180, P = 0.008), and Cluster 2 mutations (adjusted OR = 2.199, 95% CI = 1.128-4.285, P = 0.021) were independent risk factors for intraoperative HDI, while sarcopenia (adjusted OR = 0.475, 95% CI = 0.266-0.846, P = 0.012) decreased the risk. CONCLUSIONS: Body composition and genotype were associated with intraoperative haemodynamics in patients with PPGL. Our results indicated that inclusion of body composition and genotype in the overall assessment of patients with PPGL helped to predict HDI during surgery, which could assist in implementing preoperative and intraoperative measures to reduce perioperative complications.

Surgical treatment of large pheochromocytoma (>6 cm): A 10-year single-center experience.

Objective: Clinical practice guidelines recommend open adrenalectomy (OA) for large pheochromocytoma (LPCC) > 6 cm in size. Although laparoscopic adrenalectomy (LA) for the treatment of LPCC has been reported, its role remains unclear. This study aimed to compare the effectiveness of LA and OA, and summary the surgical treatment experience. Methods: Data concerning LPCC, from January 2010 to June 2019 of a single institution, were retrospectively reviewed. Altogether 82 patients with a tumor larger than 6 cm were included (52 patients in LA group and 30 patients in OA group). Groups were balanced by propensity score matching (PSM) into 15 pairs. Patients' demographics, preoperative characteristics, and prognosis were analyzed. Results: Before PSM, the OA group had larger tumor sizes (median [interquartile range, IQR]: 8.9 [7.3-10.3] vs. 7.2 [6.7-8.0] cm; p=0.000) and higher vanillylmandelic acid level (median [IQR]: 114.3 [67.8-326.4] vs. 66.6 [37.8-145.8] µmol/24 h; p =0.004) and needed a higher cumulative dose of prazosin (median [IQR]: 83.5 [37.0-154.0] vs. 38.0 [21.0-81.0] mg; p=0.028). After PSM, the baseline data showed no significant differences between both groups. The LA group had relatively more stable blood pressure in surgery, with a lower fluctuation of systolic blood pressure (mean±standard deviation [SD]: 70.9±25.1 vs. 107.4±46.2 mmHg, p=0.012) and a lower percentage of hemodynamic instability (46.7% vs. 86.7%, p=0.020). The LA group had shorter postoperative hospital stays (mean±SD: 6.4±2.7 vs. 10.1±3.4 days; p=0.003) than the OA group. Differences regarding metastasis rate (6.7% vs. 0, p=1.000) were not statistically significant between LA and OA groups. The median (IQR) follow-up time of 82 patients was 72.5 (47.0-103.5) months. Binary logistic regression showed that right-side tumors or those >8 cm in size were independent risk factors of OA. Conclusion: LA is a safe, minimally invasive procedure for LPCC and has relatively better perioperative characteristics in large medical centers. Patients with tumors on the right side or larger than 8 cm are more likely to undergo OA initially.

Value of Immunohistochemical Expression of Apelin, Succinate Dehydrogenase B, Chromogranin B, Human Epidermal Growth Factor Receptor-2, Contactin 4, and Succinyl-CoA Synthetase Subunit Beta in Differentiating Metastatic From Non-Metastatic Pheochromocytoma and Paraganglioma.

Objective: We aimed to retrospectively collect pathologically identified pheochromocytoma and paraganglioma (PPGL) tumor tissues from our center and investigate the expression of apelin and succinyl-CoA synthetase subunit beta (SUCLG2), human epidermal growth factor receptor-2 (HER2 or ERBB-2), contactin 4 (CNTN4), chromogranin B (CHGB), and succinate dehydrogenase B (SDHB) in metastatic and non-metastatic PPGLs, for exploring their roles in the diagnosis of metastatic PPGLs. Methods: A total of 369 patients with pathologically and surgically confirmed PPGLs at Xiangya Hospital, Central South University, between June 2010 and June 2020 were retrospectively included. Sixty patients-12 patients with metastatic PPGLs and 48 patients with non-metastatic PPGLs-were selected through propensity score matching (1:4) to reduce the effect of PPGL type, sex, and age. We observed and quantified the expression of apelin, SDHB, CHGB, ERBB-2, CNTN4, and SUCLG2 in paraffin-embedded samples using immunohistochemical staining. Results: No significant differences were observed between the metastatic group and non-metastatic group with respect to the expression of CNTN4 and SUCLG2. The expression of apelin, SDHB, CHGB, and ERBB-2 was significantly different between the two groups. The expression of apelin, SDHB, and CHGB was significantly lower in the metastatic group than that in the non-metastatic group (P < 0.001). ERBB-2 expression was significantly higher in the metastatic group than in the non-metastatic group (P = 0.042). Kaplan-Meier analysis revealed that patients with negative expression of apelin, SDHB, and CHGB showed significantly lower metastasis-free survival than those with positive expression. Multivariate Cox analysis revealed that SDHB and CHGB levels were independently associated with metastasis-free survival. Conclusion: The expression levels of apelin, CHGB, SDHB, and ERBB-2 may be predictive biomarkers for the diagnosis of metastatic PPGLs. Patients with negative expression of apelin, CHGB, and SDHB should be subjected to frequent postoperative follow-up procedures.

SYT8 promotes pancreatic cancer progression via the TNNI2/ERRα/SIRT1 signaling pathway.

Pancreatic cancer is a highly lethal malignancy due to failures of early detection and high metastasis in patients. While certain genetic mutations in tumors are associated with severity, the molecular mechanisms responsible for cancer progression are still poorly understood. Synaptotagmin-8 (SYT8) is a membrane protein that regulates hormone secretion and neurotransmission, and its expression is positively regulated by the promoter of the insulin gene in pancreatic islet cells. In this study, we identified a previously unknown role of SYT8 in altering tumor characteristics in pancreatic cancer. SYT8 levels were upregulated in patient tumors and contributed towards increased cell proliferation, migration, and invasion in vitro and in vivo. Increased SYT8 expression also promoted tumor metastasis in an in vivo tumor metastasis model. Furthermore, we showed that SYT8-mediated increase in tumorigenicity was regulated by SIRT1, a protein deacetylase previously known to alter cell metabolism in pancreatic lesions. SIRT1 expression was altered by orphan nuclear receptor ERRα and troponin-1 (TNNI2), resulting in cell proliferation and migration in an SYT8-dependent manner. Together, we identified SYT8 to be a central regulator of tumor progression involving signaling via the SIRT1, ERRα, and TNNI2 axis. This knowledge may provide the basis for the development of therapeutic strategies to restrict tumor metastasis in pancreatic cancer.

Machine Learning: Applications and Advanced Progresses of Radiomics in Endocrine Neoplasms.

Endocrine neoplasms remain a great threat to human health. It is extremely important to make a clear diagnosis and timely treatment of endocrine tumors. Machine learning includes radiomics, which has long been utilized in clinical cancer research. Radiomics refers to the extraction of valuable information by analyzing a large amount of standard data with high-throughput medical images mainly including computed tomography, positron emission tomography, magnetic resonance imaging, and ultrasound. With the quantitative imaging analysis and model building, radiomics can reflect specific underlying characteristics of a disease that otherwise could not be evaluated visually. More and more promising results of radiomics in oncological practice have been seen in recent years. Radiomics may have the potential to supplement traditional imaging analysis and assist in providing precision medicine for patients. Radiomics had developed rapidly in endocrine neoplasms practice in the past decade. In this review, we would introduce the general workflow of radiomics and summarize the applications and developments of radiomics in endocrine neoplasms in recent years. The limitations of current radiomic research studies and future development directions would also be discussed.

Downregulated F-Box/LRR-Repeat Protein 7 Facilitates Pancreatic Cancer Metastasis by Regulating Snail1 for Proteasomal Degradation.

Pancreatic cancer (PCa) is one of the most aggressive lethal malignancies, and cancer metastasis is the major cause of PCa-associated death. F-box/LRR-repeat protein 7 (FBXL7) regulates cancer metastasis and the chemosensitivity of human pancreatic cancer. However, the clinical significance and biological role of FBXL7 in PCa have been rarely studied. In this study, we found that the expression of FBXL7 was down-regulated in PCa tissues compared with tumor-adjacent tissues, and the low expression of FBXL7 was positively associated with cancer metastasis. Functionally, overexpression of FBXL7 attenuated PANC1 cell invasion, whereas FBXL7 silencing promoted BxPC-3 cell invasion. Forced expression of FBXL7 upregulated the expression of epithelial markers (e.g., E-cadherin) and repressed the expression of mesenchymal markers (e.g., N-cadherin and Vimentin), indicating that FBXL7 negatively regulated the epithelial-mesenchymal transition (EMT) of PCa cells. Furthermore, we identified that FBXL7 repressed the expression of Snail1, a crucial transcription factor of EMT. Mechanistically, FBXL7 bound to Snail1 and promoted its ubiquitination and proteasomal degradation. In vivo studies demonstrated that FBXL7 inhibition promotes PCa metastasis. Taken together, our findings demonstrate that FBXL7 knockdown could efficiently enhance PCa metastasis by regulating Snail1-dependent EMT.

Chronic alcohol exposure promotes HCC stemness and metastasis through ß-catenin/miR-22-3p/TET2 axis.

Hepatocellular Carcinoma (HCC) patients usually have a high rate of relapse and metastasis. Alcohol, a risk factor for HCC, promotes the aggressiveness of HCC. However, the basic mechanism is still unclear. We used HCC cells and an orthotopic liver tumor model of HCC-LM3 cells for BALB/C nude mice to study the mechanism of alcohol-induced HCC progression. We showed that chronic alcohol exposure promoted HCC cells metastasis and pulmonary nodules formation. First, we identified miR-22-3p as an oncogene in HCC, which promoted HCC cells stemness, tumor growth, and metastasis. Further, we found that miR-22-3p directly targeted TET2 in HCC. TET2, a dioxygenase involved in cytosine demethylation, has pleiotropic roles in hematopoietic stem cells self-renewal. In clinic HCC specimen, TET2 expression was not only decreased by alcohol consumption, but also inversely correlated with miR-22-3p levels. Then, we demonstrated that TET2 depletion promoted HCC cells stemness, tumor growth and metastasis. Furthermore, we identified that ß-catenin was an upstream activator of miR-22-3p. In conclusion, this study suggests that chronic alcohol exposure promotes HCC progression and ß-catenin/miR-22-3p/TET2 regulatory axis plays an important role in alcohol-promoted HCC malignancy.

Identification of novel hub genes and lncRNAs related to the prognosis and progression of pancreatic cancer by microarray and integrated bioinformatics analysis.

BACKGROUND: Pancreatic cancer (PC) is one of the most invasive and metastatic neoplasms among the fatal malignancies of the digestive system. Abnormal expression of genes and long non-coding RNAs (lncRNAs) are reportedly linked to multiple cancers. However, the lncRNA-mRNA expression profiles and their molecular mechanisms in PC progression are poorly known. This study aimed to map the hub genes and lncRNAs which might play core roles in the development of PC. METHODS: This study used microarray expression analysis to screen for both differentially expressed genes (DEGs) and differentially expressed lncRNAs (DElncRNAs) between PC and matched adjacent non-tumor (AN) tissues. In order to clarify the functional classification of DEGs, we conducted GO and KEGG pathway enrichment analyses via the Enrichr database. LncRNA-mRNA co-expressed networks were also constructed to explore the probable core regulating DEGs and DElncRNAs. Subsequently, the hub genes and lncRNAs were validated via the ONCOMINE and GEPIA databases and the co-expressed networks. RESULTS: By analyzing an mRNA-lncRNA microarray, we identified 943 mRNAs and 1,138 lncRNAs differentially expressed in PC tumors compared with the matched AN tissues. GO analysis confirmed that both up-regulated and down-regulated DEGs were enriched in multiple terms. The KEGG pathways enrichment analyses revealed that DEGs were mostly enriched in the focal adhesion and glutathione metabolism pathways, amongst others. Co-expressed networks were established to reveal the differential interactions between DEGs and DElncRNAs, and to indicate the core regulatory factors located at the core nodes of the co-expressed networks. The expression levels of potential core-regulating DEGs were validated by the GEPIA and ONCOMINE databases, and the relationship between overall survival and tumor stage and the potential core-regulating DEGs was analyzed using the GEPIA database. As a result, five genes and sixteen lncRNAs were finally considered as the hub transcripts in PC. CONCLUSIONS: This study identified DEGs and DElncRNAs between PC tumors and matched AN tissues, and these transcripts were connected with malignant phenotypes in PC through different BPs and signaling pathways. Furthermore, five hub genes and sixteen lncRNAs were identified, which are expected to represent candidate diagnostic biomarkers or potential therapeutic targets for PC.

Circular RNA circSDHC serves as a sponge for miR-127-3p to promote the proliferation and metastasis of renal cell carcinoma via the CDKN3/E2F1 axis.

BACKGROUND: There is increasing evidence that circular RNAs (circRNAs) have significant regulatory roles in cancer development and progression; however, the expression patterns and biological functions of circRNAs in renal cell carcinoma (RCC) remain largely elusive. METHOD: Bioinformatics methods were applied to screen for circRNAs differentially expressed in RCC. Analysis of online circRNAs microarray datasets and our own patient cohort indicated that circSDHC (hsa_circ_0015004) had a potential oncogenic role in RCC. Subsequently, circSDHC expression was measured in RCC tissues and cell lines by qPCR assay, and the prognostic value of circSDHC evaluated. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of circSDHC on RCC proliferation and metastasis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between circSDHC, miR-127-3p and its target genes. RESULTS: Clinically, high circSDHC expression was correlated with advanced TNM stage and poor survival in patients with RCC. Further, circSDHC promoted tumor cell proliferation and invasion, both in vivo and in vitro. Analysis of the mechanism underlying the effects of circSDHC in RCC demonstrated that it binds competitively to miR-127-3p and prevents its suppression of a downstream gene, CDKN3, and the E2F1 pathway, thereby leading to RCC malignant progression. Furthermore, knockdown of circSDHC caused decreased CDKN3 expression and E2F1 pathway inhibition, which could be rescued by treatment with an miR-127-3p inhibitor. CONCLUSION: Our data indicates, for the first time, an essential role for the circSDHC/miR-127-3p/CDKN3/E2F1 axis in RCC progression. Thus, circSDHC has potential to be a new therapeutic target in patients with RCC.

Cordycepin enhances the chemosensitivity of esophageal cancer cells to cisplatin by inducing the activation of AMPK and suppressing the AKT signaling pathway.

Although cisplatin (cDDP), is a first-line chemotherapy drug for esophageal cancer, it still has the potential to develop drug resistance and side effects. There is increasing evidence that cordycepin can work synergistically with other chemotherapy drugs. Therefore, we investigated whether combination therapy of cordycepin and cDDP may enhance the therapeutic effect of cDDP. We performed a series of functional tests to study the effect of medical treatment on esophageal cancer cells. We then used GO analysis to examine the pathways affected by treatment with cordycepin and cDDP. Next, we observed changes in the abundance of the selected pathway proteins. The in vivo animal model supported the results of the in vitro experiments. Co-treatment with cordycepin and cDDP inhibited cell growth, migration, and metastasis, as well as induced apoptosis. Cordycepin was found to effectively enhance activation of AMPK and inhibited activity of AKT. In all treatment groups, the expression levels of p-PI3K, p-Akt, p-p70S6K, Caspase-3, and Bcl-2 were significantly reduced, while the expression levels of p-AMPK, cleaved Caspase-3, and Bax increased, and the total levels of Akt, PI3K, and p70S6K levels remained unchanged. Overall, cordycepin was found to enhance the chemical sensitivity of esophageal cancer cells to cisplatin by inducing AMPK activation and inhibiting the AKT signaling pathway. Combination therapy of cordycepin and cisplatin represent a novel potential treatment of esophageal cancer.

A Comprehensive Analysis Identified the Key Differentially Expressed Circular Ribonucleic Acids and Methylation-Related Function in Pheochromocytomas and Paragangliomas.

We investigated differentially expressed circular RNAs (circRNAs) and their potential functions in pheochromocytomas and paragangliomas (PCC/PGLs). Expression levels of circRNAs in tumor and adjacent normal tissues from seven PCC/PGL patients were analyzed through RNA sequencing. Real-time PCR was conducted to verify the key candidates identified in the sequencing data. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the functions of these circRNAs. A total of 367 circRNAs were found differentially expressed between tumor and normal samples. The top three histone methylation-related circRNAs (hsa_circ_0000567, hsa_circ_0002897, and hsa_circ_0004473) and their target microRNAs (miRNAs) were identified and validated. We then mapped the circRNA-miRNA-messenger RNA (mRNA) coding-noncoding gene co-expression (CNC) networks to show the potential binding relationships between circRNAs and their targets in PCC/PGLs. The top five mRNAs, 88 miRNAs, and 132 circRNAs related to pathogenesis were utilized to map the CNC network, and we observed that the interactions of these candidates with their target miRNAs regulated histone methylation and further mediated PCC/PGL pathogenesis. This study is the first to provide the whole profile of differentially expressed circRNAs in PCC/PGLs. Our data indicate that altered circRNAs may control the pathogenesis of PCC/PGLs by regulating histone methylation processes, highlighting their role as potential biomarkers.

Long noncoding RNA-mRNA expression profiles and validation in pancreatic neuroendocrine neoplasms.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are a group of endocrine tumours arising in the pancreas and deemed to be the most common neuroendocrine tumours. The pathogenesis of pNENs remains unknown. Long noncoding RNAs (lncRNAs) are aberrantly expressed in cancers. The functional roles of lncRNAs and lncRNA-mRNA expression profiles in pNENs are undefined. The aim of this study was to identify the lncRNA and mRNA expression profiles and explore the lncRNA-mRNA co-expression networks associated with the pNENs carcinogenesis. METHOD: Differentially expressed lncRNA and mRNA in pNENs tissues from adjacent tissues were detected using human lncRNA microarray V3.0 containing 30 586 lncRNA and 26 109 coding transcripts. Probable functions for lncRNAs and mRNAs were predicted according to lncRNA-mRNA network. RESULTS: The microarray identified 2080 lncRNAs and 1771 mRNAs in pNENs tumours differentially expressed compared with the adjacent tissues. The GO terms and KEGG pathway annotation data indicated that cell projection morphogenesis, cell adhesion molecules pathway, PI3K-AKT signalling pathway, focal adhesion pathway, neuroactive ligand-receptor interaction pathways and Ras signalling pathways were significantly associated with the pNENs tumorigenesis. Co-expression network analysis revealed the differential interactions between lncRNAs and mRNAs in pNENs tumours and adjacent tissues. The genes, situated at the important nodes of the co-expression network, include ICOSLG, ENST00000512077, FGF8 and ENST00000511918. CONCLUSIONS: There were significant differences in lncRNA and mRNA expression between pNEN tumours and adjacent tissues, and these differences were associated with tumorigenesis through multiple biological processes and signalling pathways. These results provided important insights regarding lncRNA in pNENs pathogenesis and provide potential therapeutic targets.