Search

Abstract Background Pancreatic cancer (PC) is a highly malignant gastrointestinal tumor, which is characterized by difficulties in early diagnosis, early metastasis, limited therapeutic response and a grim prognosis. Therefore, it is imperative to explore potential therapeutic targets for PC. Currently, although the involvement of the Pellino E3 Ubiquitin Protein Ligase 1 (PELI1) in the human growth of some malignant tumors has been demonstrated, its association with PC remains uncertain. Methods Bioinformatics, qRT-PCR, Western blot and IHC were used to detect the expression of PELI1 in pancreas or PC tissues and cells at mRNA and protein levels. The effects of PELI1 on the proliferation and metastatic ability of pancreatic cancer in vitro and in vivo were investigated using CCK8, cloning formation, EdU, flow cytometry, IHC, Transwell assay, wound healing, nude mice subcutaneous tumorigenesis and intrasplenic injection to construct a liver metastasis model. The interactions of PELI1 with proteins as well as the main functions and pathways were investigated by protein profiling, Co-IP, GST-pull down, Immunofluorescence techniques, immunohistochemical co-localization and enrichment analysis. The rescue experiment verified the above experimental results. Results The mRNA and protein expression levels of PELI1 in PC tissues were upregulated and were associated with poor prognosis of patients, in vitro and in vivo experiments confirmed that PELI1 can affect the proliferation and metastatic ability of PC cells. Co-IP, GST-pull down, and other experiments found that PELI1 interacted with Ribosomal Protein S3 (RPS3) through the FHA structural domain and promoted the polyubiquitination of RPS3 in the K48 chain, thereby activates the PI3K/Akt/GSK3β signaling pathway. Moreover, ubiquitinated degradation of RPS3 further reduces Tumor Protein P53 (p53) protein stability and increases p53 degradation by MDM2 Proto-Oncogene (MDM2). Conclusion PELI1 is overexpressed in PC, which increased ubiquitination of RPS3 proteins and activates the PI3K/Akt/GSK3β signaling pathway, as well as reduces the protective effect of RPS3 on p53 and promotes the degradation of the p53 protein, which facilitates the progression of PC and leads to a poor prognosis for patients. Therefore, PELI1 is a potential target for the treatment of PC.

The pathogenic mechanisms of pancreatic cancer (PC) are still not fully understood. Ubiquitination modifications have a crucial role in tumorigenesis and progression. Yet, the role of MINDY2, a member of the motif interacting with Ub-containing novel DUB family (MINDY), as a newly identified deubiquitinating enzyme, in PC is still unclear. In this study, we found that MINDY2 expression is elevated in PC tissue (clinical samples) and was associated with poor prognosis. We also found that MINDY2 is associated with pro-carcinogenic factors such as epithelial-mesenchymal transition (EMT), inflammatory response, and angiogenesis; the ROC curve suggested that MINDY2 has a high diagnostic value in PC. Immunological correlation analysis suggested that MINDY2 is deeply involved in immune cell infiltration in PC and is associated with immune checkpoint-related genes. In vivo and in vitro experiments further suggested that elevated MINDY2 promotes PC proliferation, invasive metastasis, and EMT. Meanwhile, actinin alpha 4 (ACTN4) was identified as a MINDY2-interacting protein by mass spectrometry and other experiments, and ACTN4 protein levels were significantly correlated with MINDY2 expression. The ubiquitination assay confirmed that MINDY2 stabilizes the ACTN4 protein level by deubiquitination. The pro-oncogenic effect of MINDY2 was significantly inhibited by silencing ACTN4. Bioinformatics Analysis and Western blot experiments further confirmed that MINDY2 stabilizes ACTN4 through deubiquitination and thus activates the PI3K/AKT/mTOR signaling pathway. In conclusion, we identified the oncogenic role and mechanism of MINDY2 in PC, suggesting that MINDY2 is a viable candidate gene for PC and may be a therapeutic target and critical prognostic indicator.

Abstract Pancreatic cancer (PC) is a common digestive system carcinoma with high mortality rate mostly due to aberrant growth and distant metastasis. Current researches demonstrated that Family Sequence Similarities (FAMs) have been involving in tumor development, and which subfamily has the function of promoting or inhibiting tumors and its in-depth molecular mechanism remains unclear. Based on the Gene Expression Omnibus (GEO), the Gene Expression Profiling Interactive Analysis (GEPIA2), we observed that FAM126A is in high expressed level among PC tissues and contributes to worse progression of PC, which was validated by PC tissue microarray. Function assay indicated that overexpression of FAM126A accelerates PC cell proliferation, invasion and migration in vitro, as well as liver cancer metastasis in vivo. Further, we found that FAM126A induces epithelial-mesenchymal transition (EMT), including the downregulation of E-cadherin epithelial marker expression, and the upregulation of N-cadherin, Vimentin, and Snail, mesenchymal marker expression. By co-localization and co-immunoprecipitation assays, we confirmed that FAM126A directly interacts with ENO1, which was a key activator of the PI3K/AKT signaling pathway. Furthermore, ENO1 knockdown reversed cell proliferation, migration, and invasion of PC cells promoted by FAM126A overexpression in vitro and in vivo. In general, these results verified FAM126A is an oncogene interacting with ENO1 in PC by activating PI3K/AKT signaling pathway.

ObjectiveHepatocellular carcinoma (HCC) is one of the most prevalent types of cancer worldwide. Shugoshin 1 (SGOL1) plays a crucial role in cell mitosis and its aberrant expression level in human tumors has shown to promote chromosomal instability (CIN) and accelerate tumor growth. SGOL1 expression level in HCC cells and tissues, whether it has an influence on HCC patients’ prognosis, and its mechanism of action have not yet been studied.MethodsWe carried out the bioinformatics analysis of SGOL1 expression level and survival analysis in 8 different malignancies, including HCC. In addition, we analyzed SGOL1 expression level in HCC tissues, as well as HCC patients’ clinical features, enrichment analysis of SGOL1 function and mechanism of action in HCC and tumor immune cells. The effects of SGOL1 expression level and cell viability on HCC were confirmed by in vitro cytological assays.ResultsIt was found that SGOL1 mRNA expression level was significantly higher in several tumor tissues, including HCC, than in corresponding normal tissues, and the elevated SGOL1 expression level was strongly associated with HCC patients’ poor prognosis. It was also revealed that SGOL1 expression level in HCC tissue was positively correlated with disease stage, tumor grade, and tumor size, and the results of multivariate logistic regression analysis showed that SGOL1 was one of the independent influential factors of the prognosis of HCC. Enrichment analysis revealed that SGOL1 expression level in HCC tissue was mainly associated with tumor proliferation, cell cycle, and other factors. The results of the immune infiltration analysis indicated that SGOL1 expression level was associated with immune cell infiltration and immune checkpoints in HCC. In vitro experiments demonstrated the high SGOL1 expression level in HCC tissues and cells, and silencing of SGOL1 resulted in altered cell cycle markers and decreased proliferation, invasion, and migration of HCC cells.ConclusionThe findings revealed that SGOL1 is highly expressed in HCC tissues, it is a biomarker of a poor prognosis, which may be related to immune cell infiltration in HCC, and may enhance the proliferation, invasion, and migration of HCC cells. The results may provide new insights into targeted treatment of HCC and improve HCC patients’ prognosis.

Cancer stem cells (CSCs) comprise a subset of tumor cells that can initiate tumorigenesis and promote tumor advance. A previous study showed that the expression of FBXW7 in hepatocellular carcinoma (HCC) clinical samples was lower than that in the adjacent nontumor tissues and was negatively correlated with the invasion and migration of HCC cells. However, the biological characteristics and the underlying molecular mechanisms of FBXW7 in HCC stemness are yet to be elucidated. In present study, we found that FBXW7 participates in the self-renewal, tumorigenicity, sorafenib therapy, and stem cell-like properties of HCC cells in vivo and in vitro. The upregulation of FBXW7 inhibited the stemness and reduced the tumorigenicity and drug resistance of HCC cells. Mechanistically, proteins binding to FBXW7 were identified by coimmunoprecipitation and protein colocalization assays. We confirmed ACTL6A as a novel downstream target for FBXW7. The in vivo ubiquitination assay showed that FBXW7 repressed HCC malignancy by regulating the oncogenic activity of ACTL6A in a ubiquitin-dependent manner. Furthermore, we found that ACTL6A overexpression inversed the self-renewal abilities and tumorigenic abilities depressed by overexpressing FBXW7. The current findings suggested that FBXW7 reduces the stemness of HCC cells by targeting and degrading ACTL6A and provides a novel target for the diagnosis and treatment of HCC.

Long non-coding RNAs (lncRNAs) have been shown to participate in the development and progression of several different types of cancer. Past studies indicated that lncRNA MAFG-antisense 1 (AS1) promotes colorectal cancer. However, the role of MAFG-AS1 in hepatocellular carcinoma (HCC) remains unclear. The aim of the present study is to examine the effect of lncRNA MAFG-AS1 on drug resistance HCC. The results indicated that MAFG-AS1 is upregulated in drug-resistant cells. Further, MAFG-AS1 promotes growth and migration of HCC by upregulating STRN4 through absorbing miR-3196. Thus, LncRNA MAFA-AS1 may become a novel target to treat HCC patients.

Background. Expression of long noncoding RNA (lncRNA) ELF3 antisense RNA 1 (ELF3-AS1) is observed in some cancers, while its role in hepatocellular carcinoma (HCC) is unclear. The study aimed to investigate the relationship between ELF3-AS1 and HCC based on database, bioinformatics, and statistical analysis. Methods. In this study, Kruskal–Wallis test, Wilcoxon sign-rank test, logistic regression, Kaplan–Meier method, Cox regression analysis, gene set enrichment analysis (GSEA), and immunoinfiltration analysis were used to assess the relationship between ELF3-AS1 expression and clinical characteristics of HCC patients, the relationship between ELF3-AS1 expression and prognosis of HCC patients, and the possible functions of ELF3-AS1 in HCC. Results. High expression of ELF3-AS1 in patients with HCC was related to T stage (P

MicroRNAs belong to a series of noncoding RNAs and have diverse roles in several biological processes. The association between aberrant microRNA expression and tumorigenesis is complex and remains to be fully elucidated. The present study investigated whether microRNA (miR) -526a can suppress the progression of hepatocellular carcinoma (HCC) in vitro and in vivo. Reverse transcription-quantitative polymerase chain reaction, luciferase reporter assay, invasion assay, western blotting and in vivo implantation were used to investigate the potential function of miR-526a. The present study observed that the level of miR-526a was downregulated in HCC tissues and well-established cell lines. In addition, the ectopic introduction of miR-526a into Huh7 and HepG2 cells significantly attenuated HCC tumorigenesis, including proliferation, migration and invasion. The growth of tumor xenografts was also inhibited following transfection with miR-526a. Using overlapping strategies, p21-activated kinase 7 (PAK7) was predicted to be a target for miR-526a, and this was verified experimentally. An inverse correlation was found between miR-526a and PAK7 in HCC tissues. The results of the present study revealed a novel function of miR-526a and may provide crucial insight into therapeutic interventions targeting microRNAs. [ABSTRACT FROM AUTHOR]