Search

Supplemental material for "Fusion oncogenes in patients with locally advanced or distant metastatic differentiated thyroid cancer"

Background: There was increasing evidence showing that ARID1A alterations correlated with higher tumor mutational burden, but there were limited studies focusing on the adaptive mechanisms for tumor cells to survive under excessive genomic alterations. Materials & methods: To further explore the adaptive mechanisms under ARID1A alterations, we performed RNA sequencing in ARID1A knockdown hepatocellular carcinoma cell lines, and demonstrated that decreased expression of ARID1A controlled global ribosomal proteins synthesis. The results were further confirmed by quantitative reverse transcription-PCR and bioinformatic analysis in The Cancer Genome Atlas Liver Hepatocellular Carcinoma database. Conclusion: The present study was the first to demonstrate that ARID1A might be involved in the translation pathway and served as an adaptive mechanism for tumor cells to survive under stress.

Over the years, molecular subtypes based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) status have been observed to effectively guide decision-making for the optimal treatment of patients with breast carcinoma (BRCA). However, despite this progress, there are still more than 41,000 BRCA-related fatalities each year in the United States. Moreover, effective drug targets for triple-negative breast carcinoma (TNBC) are still lacking. Given its high mortality rate, it is necessary to investigate more biomarkers with prognostic and pathological relevance in BRCA. In our study, we examined the expression patterns and prognostic implications of transmembrane P24 trafficking protein 9 (TMED9) in BRCA using multiple public cohorts and BRCA specimens collected from Shanghai General Hospital. In addition to this, in vitro experiments were also performed to evaluate the effects of TMED9 expression in BRCA cell proliferation and migration. Our results have demonstrated that a high expression of TMED9 promoted BRCA cell proliferation and migration and predicted poor prognosis in patients with BRCA. In conclusion, TMED9 is a potential prognostic indicator and a possible drug target of BRCA.

Purpose Hepatocellular carcinoma (HCC) is one of the most devastating diseases worldwide. Limited performance of clinicopathologic parameters as prognostic factors underscores more accurate and effective biomarkers for high-confidence prognosis that guide decision-making for optimal treatment of HCC. The aim of the present study was to establish a novel panel to improve prognosis prediction of HCC patients, with a particular interest in transcription factors (TFs). Materials and methods A TF-related prognosis model of liver cancer with data from ICGC-LIRP-JI cohort successively were processed by univariate and multivariate Cox regression analysis. Then, for evaluating the prognostic prediction value of the model, receiver operating characteristic (ROC) curve and survival analysis were performed both with internal data from the International Cancer Genome Consortium (ICGC) and external data from The Cancer Genome Atlas (TCGA). Furthermore, we verified the expression of three genes in HCC cell lines by Western blot and qPCR and protein expression level by IHC in liver cancer patients' sample. Finally, we constructed a TF clinical characteristics nomogram to furtherly predict liver cancer patient survival probability with TCGA cohort. Results By Cox regression analysis, a panel of 15 TFs (ZNF331, MYCN, AHRR, LEF1, ZNF780A, POU1F1, DLX5, ZNF775, PLSCR1, FOXK1, TAL2, ZNF558, SOX9, TCFL5, GSC) was identified to present with powerful predictive performance for overall survival of HCC patients based on internal ICGC cohort and external TCGA cohort. A nomogram that integrates these factors was established, allowing efficient prediction of survival probabilities and displaying higher clinical utility. Conclusion The 15-TF panel is an independent prognostic factor for HCC, and 15 TF-based nomogram might provide implication an effective approach for HCC patient management and treatment.

Globally, hepatocellular carcinoma (HCC) has a dismal prognosis and studies have shown that accurate prognostic risk assessment can have clinically significant benefits for patients with HCC patients. After successively performing univariate Cox regression, Lasso regression, and stepwise multivariate Cox regression analysis, three pyroptosis gene (GPX4, NLRP1, and NLRP6) were selected to construct and validate the prognostic model of HCC based on public data. The expression pattern and prognostic implication of GPX4 in HCC was validated by immunohistochemistry staining in HCC specimens collected from Affiliated Hospital of Jining Medical University. A nomogram combined model and clinical characteristics was plotted after the prognostic predictive value of model was validated with receiver operating characteristic curves and Kaplan-Meier survival analysis. Our results indicate that assessing pyroptosis gene expression may be useful to predict the prognosis of HCC patients by enhancing antitumor immunity.

Overexpression of DTYMK is related with tumorigenesis and progression in several human tumors. However, the role of upregulated DTYMK in hepatocellular carcinoma (HCC) patients still remains unclear. In this study, the DTYMK expression in HCC tumors was evaluated in three GEO series (GSE14520, GSE54236, GSE63898), TCGA-LIHC, and ICGC-IRLR-JP cohorts. Survival analysis of DTYMK based on TCGA-LIHC and ICGC-LIRI-JP cohorts was conducted. We found that DTYMK was dramatically upregulated in tumor tissue compared with that in adjacent liver tissue. Kaplan-Meier analysis revealed that high expression of DTYMK in HCC patients' tumor tissue was significantly corresponded to worse overall survival (OS) (P < 0.05). Further analysis showed that overexpressing DTYMK led to poor relapse free survival (RFS) and disease-specific survival (DSS) (all P < 0.05). In conclusion, DTYMK is upregulated in tumors and correlated with poor prognosis in HCC patients. In our report, DTYMK is higher expression in HCC cancer tissue and cell line than tumor adjacent tissue and normal liver cell line. Knocking down DTYMK can inhabit tumor cell proliferation by interfering cell cycle, whereas overexpression of DTYMK can promote tumor cell proliferation. These findings indicate that upregulation of DTYMK enhances tumor growth and proliferation by promoting cell cycle.

Background Anomalous expression of glucose transporters (GLUTs) has been observed in a variety of tumor tissues. Although GLUT factors have been shown to have prognostic value for some cancer types, detailed bioinformatics investigation of the factors contributing to the prognostic prediction for patients with breast cancer (BC) has not yet been performed. Methods In this study, we examined the transcription levels of GLUT1, GLUT3, and GLUT4 and their associations with prognostic clinical data in patients with BC from the ONCOMINE database, using gene expression profiling interactive analysis (GEPIA), Kaplan-Meier (KM) plotter, and cBioPortal online tools. Results The transcription level of GLUT1 was significantly higher in the BC samples than in the normal tissues, whereas the levels of GLUT3 and GLUT4 were lower in the BC samples. The expression levels of GLUT1 and GLUT3 were associated with the cancer clinical stage. Consistently, survival analysis demonstrated that a high expression level of GLUT1 was associated with low relapse-free survival (RFS) in patients with BC, whereas high GLUT3 and GLUT4 levels predicted a longer RFS in these patients. Conclusions Overall, these results suggest GLUT1 as an effective target of precision therapy, while GLUT3/4 are novel biomarkers for the prognosis of patients with BC.

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. However, regulation of CSCs stemness is not entirely understood. Here, we report that TSPAN8 expression is upregulated in breast CSCs, promotes the expression of the stemness gene NANOG, OCT4, and ALDHA1, and correlates with therapeutic resistance. Mechanistically, TSPAN8 interacts with PTCH1 and inhibits the degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3. This results in the translocation of SMO to cilia, downstream gene expression, resistance of CSCs to chemotherapeutic agents, and enhances tumor formation in mice. Accordingly, expression levels of TSPAN8, PTCH1, SHH, and ATXN3 are positively correlated in human breast cancer specimens, and high TSPAN8 and ATXN3 expression levels correlate with poor prognosis. These findings reveal a molecular basis of TSPAN8-enhanced Sonic Hedgehog signaling and highlight a role for TSPAN8 in promoting cancer stemness., Tetraspanin 8 (TSPAN8) has been implicated in a number of different tumours, but the underlying mechanisms remain unclear. Here, in breast cancer the authors highlight a role for TSPAN8 in promoting tumorigenesis through the activation of Hedgehog signalling.

Objective: Based on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER-2), and proliferation cell nuclear antigen (Ki-67) status, breast cancer (BC) can be divided into several molecular sub-types. The patterns of these biological receptors may change during the course of progression and metastasis which could lead to new treatment strategies accordingly. Method: The present multi-center-based clinical data investigated the discordance patterns of molecular features in Chinese BC patients between primary tumors and distant metastasis. 151 pathologically confirmed BC patients were enrolled. The comparison of the statuses of ER, PR, HER-2, and the Ki-67 index by the IHC and/or FISH method was performed. Results: The discordance rate in one or more molecular markers was 52.4% and varied between primary and metastatic lesions. The most common transformation pattern was the loss of ER and PR. On the other hand, the ER-positive patients have the longest OS. Patients with ER changing from positive to negative have the shortest OS. The patients with PR changing from negative to positive have the longest OS, while PR-negative patients have the shortest OS. The median DFI (disease-free interval) was 54.93 months in this study. ER, PR, and HER-2 transformation rates are common in patients with DFI < 2 years than in patients with DFI ≥ 5 years. For patients with an ER-positive expression in metastatic lesions, a significantly prolonged PFS was observed (P < 0.05) in those receiving endocrine treatment. Conclusion: The transformation of molecular subtyping status was identified between primary and corresponding relapse lesions and was used for determining the treatment strategies and prognosis prediction in advanced BC patients.

The mechanism and function of TSPAN8 on the invasion and metastasis of cancer cells is poorly understood. In present study, we demonstrated that TSPAN8 over-expressed in pancreatic cancer (Paca) tissues (37.98%) comparing with normal tissue (0%). TSPAN8 expression levels were reversely correlated with the overall survival time of Paca patients (p = 0.021). In vitro, over-expressed or knockdown TSPAN8 expression in Paca cells SW1990 or Capan-2 and AsPC-1 modulated invasion, immigration and clone formation ability. Mechanistically, we revealed that SOX9, a downstream transcription factor of EGFR signaling, activated TSPAN8 transcription under EGF condition. Meanwhile, we uncovered a previously uncharacterized mechanism underlying EGF-dependent Paca cells invasion and migration. In brief, TSPAN8 was phosphorylated at Ser129 by AKT, resulting in the binding of TSPAN8 with BCAFL1, TSPAN8 entering nucleus and regulating the EPS8L3 transcription, remodeling of cytoskeleton, and enhancing cell invasion and migration. By single cell seq analysis of Paca cells derived from patients and tissue array assay, we validated that the EGFR and EPS8L3 expression in mRNA and protein level were highly correlated with TSPAN8 expression. In vivo and in vitro study demonstrated that EPS8L3 depletion or overexpression rescued the invasion ability induced by TSPAN8. These findings reveal a molecular basis of EGF-TSPAN8-EPS8L3 signaling and highlight the critical role of TSPAN8 in tumor metastasis. Citation Format: Junjian Li, Rongxuan Zhu, Gaoda Ju, Weiyu Ge, Mengyi Jiang, Tianhao Zhou, Hongxia Wang. TSPAN8-EPS8L3 signaling play a role in EGF-dependent pancreatic cancer cell invasion and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2848.