CK2B is a Prognostic Biomarker and a Potential Drug Target for Hepatocellular Carcinoma.

BACKGROUND: Although casein kinase II subunit beta (CK2B) was previously reported to be involved in human cancers, such as hepatocellular carcinoma (HCC), there has been no systematic assessment of CK2B in HCC. OBJECTIVE: To assess the potential function of CK2B as a prognostic biomarker and possible druggable target in HCC. METHODS: The Cancer Genome Atlas database was accessed to investigate the potential oncogenic and prognostic roles of CK2B in HCC. Diverse analytical methods were used to obtain a fuller understanding of CK2B, including CIBERSORT, The Tumor Immune Estimation Resource (TIMER), gene set enrichment analyses (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene ontology (GO). Furthermore, the Comparative Toxicogenomic Database (CTD) was used to identify potential drugs to treat CK2B-overexpressing HCC. Patents for these drugs were reviewed using Patentscope® and Worldwide Espacenet®. RESULTS: Upregulated CK2B expression was markedly associated with more aggressive pathological features, including G3, G4 (vs. G1, G2), and T2, T3 (vs. T1). Kaplan-Meier survival curves indicated that patients with HCC with higher expression of CK2B had worse overall survival (P = 0.005), progression-free interval (P = 0.001), and disease-specific survival (P = 0.011). GO and KEGG analysis revealed that CK2B dysregulation affects mitotic chromosome condensation, protein stabilization and binding, regulation of signal transduction of p53 class mediator, and cancer-related pathways. GSEA identified six well-known pathways, including MAPK, WNT, Hedgehog, and TGFß signaling pathways. Finally, CTD identified six compounds that might represent targeted drugs to treat HCC with CK2B overexpression. A review of patents indicated these compounds showed promising anticancer results; however, whether CK2B interacts with these drugs and improves drug outcomes for patients with HCC was not confirmed. CONCLUSION: CK2B is a biomarker for HCC prognosis and could be a potential new drug target. Moreover, the association between infiltrating immune cells and CK2B in the HCC tumor microenvironment might provide a solid basis for further investigation and a potent strategy for immunotherapy of HCC.

Association of metabolic syndrome and the risk of bladder cancer: A prospective cohort study.

Background: Metabolic syndrome (MetS) and its components have been shown as risk factors for several solid cancers. However, current epidemiological evidence about the relevance of MetS and bladder cancer risk was limited. Methods: We conducted a prospective cohort study of 476,986 participants with undiagnosed bladder cancer based on the UK Biobank. MetS was defined as the presence of at least three of the five selected indicators: hypertension, central obesity, raised triglyceride, reduced HDL-cholesterol, and raised fasting plasma glucose. Bladder cancer has been identified through contact with the British Cancer Registry (median follow-up time: 6.6 years). We assessed hazard ratio (HR) and 95% confidence interval (CI) through Cox proportional hazard regression after adjusting for demographic and lifestyle factors. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method. Results: During a follow-up of 3,112,566 person-years, 487 cases of bladder cancer were ascertained. MetS (HR = 1.32, 95% CI = 1.08-1.61), central obesity (HR = 1.39, 95% CI = 1.15-1.68), dyslipidemia for HDL cholesterol (HR = 1.31, 95% CI = 1.04-1.66), and hyperglycemia (HR = 1.44, 95% CI = 1.16-1.79) were associated with elevated risk of bladder cancer. Bladder cancer risk increased with the number of MetS components. In stratified analyses, MetS showed similar effects in bladder cancer independently with sex, age, cigarette and alcohol use, physical activity, and dietary factors. Higher waist circumference, BMI, fasting blood glucose, and glycosylated hemoglobin were independently associated with increased risk of bladder cancer, with no evidence against non-linearity. Conclusion: MetS might be an independent risk factor for bladder cancer. Our findings highlighted the importance of individualized management of MetS components for preventing bladder cancer.

The Prognostic and Drug-targeting Value of Lymphoid Enhancer-binding Factor-1 in Hepatocellular Carcinoma.

BACKGROUND: Lymphoid Enhancer-Binding Factor-1 (LEF1) was previously reported to contribute to a variety of malignancies, including Hepatocellular Carcinoma (HCC). However, its role in HCC is poorly understood. OBJECTIVES: To explore the role of LEF1 in HCC, including its prognostic and drug-targeting value. METHODS: The LEF1 expression and patient characteristics were investigated. The associations between clinical characteristics and LEF1 were analyzed using both univariate and multivariate logistic regression. Cox regression and Kaplan-Meier curves were used to explore the clinicopathological factors related to overall survival in patients with HCC. A nomogram to predict the survival rate was constructed and validated. The Kyoto Encyclopedia of Genes and Genomes database (KEGG) was used to explore the function of LEF1. Gene Set Enrichment Analysis (GSEA) was also performed using The Cancer Genome Atlas dataset. Furthermore, compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC were identified using the Comparative Toxicogenomics Database (CTD), patents about these drugs in HCC were also reviewed through Worldwide Espacenet® and Patentscope®. RESULTS: Increased expression of LEF1 was significantly associated with high histological grade of HCC (odds ratio (OR) = 2.521 for grade (G) 2 vs. G1, OR = 2.550 for G3 vs. G1, OR = 7.081 for G4 vs. G1, all P < 0.05). A Kaplan-Meier survival curve showed that HCC patients with LEF1 overexpression had a poor prognosis compared with those with normal LEF1 expression (P = 0.025). Multivariate Cox regression analysis revealed that LEF1 is an independent prognostic factor for the overall survival of patients with HCC (Hazard Ratio (HR) = 1.095; P = 0.04). The constructed nomogram to predict the survival rate produced a statistically significant prediction (area under the curve (AUC) = 86.68). In addition, Gene Ontology (GO) and KEGG analysis of genes co-expressed with the protein showed that LEF1 was associated with transcriptional regulation. GSEA suggested that the cell cycle, the WNT signaling pathway, and the NOTCH signaling pathway may be the key pathways regulated by LEF1 in HCC. Furthermore, the Comparative Toxicogenomics Database (CTD) identified nine compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC. Patent reviews suggested that these drugs may show some efficacy in HCC, but whether these drugs interact with LEF1 and improve the prognosis for patients with HCC remains to be explored. CONCLUSION: LEF1 is a latent prognostic molecular biomarker of HCC. The cell cycle, and WNT and NOTCH signaling pathways are regulated by LEF1 in HCC. LEF1 could be a potential drug target for HCC.

Value of Cytokine Expression in Early Diagnosis and Prognosis of Tumor Metastasis.

Objective: To investigate the association of the plasma level of cytokines and blood routine indexes with clinical characteristics in patients with cancer. Methods: We analyzed plasma samples derived from 134 cancer patients. Interleukins (IL) 1ß, 2, 4, 5, 6, 8, 10, 12p70, 17, IFN-γ, IFN-α, and TNF-α, and blood routine indexes were measured. The associations of the levels of cytokine and blood routine indexes with demographic and clinical characteristics of cancer patients were analyzed. Partial least-squares discriminant analysis was employed to identify cancer metastasis using these plasma cytokine metrics as input. We compared the predictive effectiveness of numeric machine learning algorithms using these indexes and showed a promising model implemented with random forest. Results: Plasma levels of IL-6 and IL-8 in cancer patients with metastases were higher than those without metastases (P < 0.05). Cancer patients without metastases had significantly higher levels of plasma IL-12p70 and percentage of lymphocytes as compared with those with metastases (P < 0.05). Our random forest model showed the highest prediction performance (upper quantile AUC, 0.885) among the six machine learning algorithms we evaluated. Conclusion: Our findings suggest that plasma levels of IL-6, IL-8, and IL-12p70 and the percentage of lymphocytes could predict the recurrence, metastasis, and progression of cancer. Our findings will provide guidance for tumor monitoring and treatment.

A case study of combined neoadjuvant chemotherapy and neoadjuvant immunotherapy in resectable locally advanced esophageal cancer.

BACKGROUND: The prognosis of patients under existing neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy requires improvement. Whereas programmed cell death 1 (PD-1) inhibitors have shown promising response in advanced esophageal cancer, they have not been used in the perioperative treatment of resectable locally advanced esophageal cancer. Whether immunotherapy can be incorporated into neoadjuvant therapy has became a challenging question for researchers. CASE PRESENTATION: We present a case of a 65-year-old male who had a history of progressive dysphagia for approximately 1 month. He underwent pertinent studies including computed tomography (CT)，gastroscopy，and pathological biopsy resulting in a diagnosis of medium-low differentiated squamous carcinoma of the thoracic segment of the esophagus (cT2N2M0 stage III). After 4 cycles of neoadjuvant chemotherapy combined with immunotherapy, gastroscopy showed the lesion in the esophagus was no longer present. Subsequently, the patient received thoracoscopic radical resection of esophageal cancer and achieved a pathological complete response (pCR) in postoperative pathological evaluation. During the whole treatment, no adverse effect was recorded and to date no evidence of recurrence has been recorded. CONCLUSION: Our report suggest that neoadjuvant chemotherapy combined with immunotherapy not only improve the R0 resection and pCR rate in patients with resectable locally advanced esophageal cancer, but also the adverse effects are within the control range. However, the selection of therapeutic strategy, predictors of response to treatment, and interval time between neoadjuvant treatment and surgery still await more reliable evidence-based studies with large prospective samples.

Prognostic and Therapeutic Values of Autophagy-related Genes in Triple-negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with a poor prognosis. Therefore, it is imperative to develop new prognostic or therapeutic biomarkers for TNBC. OBJECTIVES: To explore the prognostic and therapeutic values of autophagy-related genes (ARGs) in TNBC. METHODS: Overall, 157 TNBC patients' data were obtained from The Cancer Genome Atlas database, and the ARGs were acquired from the Human Autophagy Database. Differentially expressed ARGs (DEGs) between tumor and normal tissues were identified, and the prognostic ARGs were developed using R software. Kaplan-Meier survival curves and receiver operating characteristic (ROC) curves were both used to evaluate the accuracy of the signature. Patents about prognostic ARGs were reviewed through Worldwide Espacenet® and Patentscope®. RESULTS: We obtained 28 DEGs and two prognostic ARGs (EIF4EBP1 and PARP1). The Kaplan- Meier survival curves showed that the survival rate of patients with low 2-ARG signature risk score was significantly higher than that of patients with high-risk score (P =0.003). ROC at 5 years indicated that the signature had good prognostic accuracy (AUC =0.929). The signature was independent of T, N, M, and TNM stages (P <0.05). The patent review suggested that many mTOR inhibitors alone or in combination with another anticancer agent have been provided for the treatment of many cancers and shown promising results. No drug patents about PARP1 overexpression were disclosed. CONCLUSION: We developed a 2-ARG signature (EIF4EBP1 and PARP1), which was an independent prognostic biomarker for TNBC. As EIF4EBP1 was upregulated in TNBC, mTOR inhibitors which blocked the mTOR/4EBP1/eIF4E pathway, may be a promising therapeutic strategy for TNBC.

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation.

BACKGROUND: Metastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC). Metastasis-initiating CTCs manage to maintain intravascular survival under anoikis, immune attack, and importantly shear stress; however, the underlying mechanisms remain poorly understood. METHODS: In view of the scarcity of CTCs in the bloodstream, suspended colorectal cancer cells were flowed into the cyclic laminar shear stress (LSS) according to previous studies. Then, we detected these suspended cells with a CK8+/CD45-/DAPI+ phenotype and named them mimic circulating tumour cells (m-CTCs) for subsequent CTCs related researches. Quantitative polymerase chain reaction, western blotting, and immunofluorescence were utilised to analyse gene expression change of m-CTCs sensitive to LSS stimulation. Additionally, we examined atonal bHLH transcription factor 8 (ATOH8) expressions in CTCs among 156 CRC patients and mice by fluorescence in situ hybridisation and flow cytometry. The pro-metabolic and pro-survival functions of ATOH8 were determined by glycolysis assay, live/dead cell vitality assay, anoikis assay, and immunohistochemistry. Further, the concrete up-and-down mechanisms of m-CTC survival promotion by ATOH8 were explored. RESULTS: The m-CTCs actively responded to LSS by triggering the expression of ATOH8, a fluid mechanosensor, with executive roles in intravascular survival and metabolism plasticity. Specifically, ATOH8 was upregulated via activation of VEGFR2/AKT signalling pathway mediated by LSS induced VEGF release. ATOH8 then transcriptionally activated HK2-mediated glycolysis, thus promoting the intravascular survival of colorectal cancer cells in the circulation. CONCLUSIONS: This study elucidates a novel mechanism that an LSS triggered VEGF-VEGFR2-AKT-ATOH8 signal axis mediates m-CTCs survival, thus providing a potential target for the prevention and treatment of hematogenous metastasis in CRC.