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Background. Pancreatic carcinoma is a malignant tumor with a high fatality rate, and the increased resistance of pancreatic carcinoma to chemotherapy has become a difficult problem in clinical practice. Hence, it is imperative to develop an effective treatment for pancreatic cancer. Sestrins are a class of stress-induced proteins that have antioxidation functions, regulating cell growth and metabolism. Curcumin is a natural pigment isolated from turmeric. Several studies have also suggested that this molecule has multiple pharmacological effects, such as anti-inflammatory, antioxidant, and antitumor effects. However, there are insufficient studies on curcumin cooperating with the sestrin family to inhibit tumors, and the mechanism is still unclear. Our aim was to observe the potential anticancer effects of curcumin combined with the sestrin family on pancreatic carcinoma and probe its possible molecular mechanisms. Methods. Lentiviral infection, real-time fluorescence quantitative PCR assays, Cell Counting Kit-8 assays, real-time cell analysis technology, colony formation assays, wound healing assays, Transwell invasion assays, protein extraction, and western blots (WBs) were used to evaluate the effect of curcumin combined with sestrin2 on the proliferation, invasion, and migration of pancreatic carcinoma cells. Results. The results revealed that curcumin cooperated with sestrin2 to significantly suppress pancreatic cancer. In addition, we determined that sestrin2 cooperated with curcumin to inhibit pancreatic cancer by specifically targeting Nrf2/Keap1/HO-1/NQO-1. Conclusion. These findings clarify that curcumin-mediated synergistic targeting of sestrin2 is a potentially valuable treatment for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common type among primary liver cancers (PLC). With its poor prognosis and survival rate, it is necessary for HCC patients to have a long-term follow-up. We believe that there are currently no relevant reports or literature about nomograms for predicting the cancer-specific mortality of HCC patients. Therefore, the primary goal of this study was to develop and evaluate nomograms to predict cancer-specific mortality and overall mortality. Data of 45,158 cases of HCC patients were collected from the Surveillance, Epidemiology, and End Results (SEER) program database between 2004 and 2013, which were then utilized to develop the nomograms. Finally, the performance of the nomograms was evaluated by the concordance index (C-index) and the area under the time-dependent receiver operating characteristic (ROC) curve (td-AUC). The categories selected to develop a nomogram for predicting cancer-specific mortality included marriage, insurance, radiotherapy, surgery, distant metastasis, lymphatic metastasis, tumor size, grade, sex, and the American Joint Committee on Cancer (AJCC) stage; while the marriage, radiotherapy, surgery, AJCC stage, grade, race, sex, and age were selected to develop a nomogram for predicting overall mortality. The C-indices for predicted 1-, 3-, and 5-year cancer-specific mortality were 0.792, 0.776, and 0.774; the AUC values for 1-, 3-, and 5-year cancer-specific mortality were 0.830, 0.830, and 0.830. The C-indices for predicted 1-, 3-, and 5-year overall mortality were 0.770, 0.755, and 0.752; AUC values for predicted 1-, 3-, and 5-year overall mortality were 0.820, 0.820, and 0.830. The results showed that the nomograms possessed good agreement compared with the observed outcomes. It could provide clinicians with a personalized predicted risk of death information to evaluate the potential changes of the disease-specific condition so that clinicians can adjust therapy options when combined with the actual condition of the patient, which is beneficial to patients. [ABSTRACT FROM AUTHOR]

Increasing evidences have suggested that natural killer (NK) cells in the tumor microenvironment are involved in the regulation of cancer development. However, the potential biological roles and regulatory mechanisms of NK cells in pancreatic cancer (PC) remain unclear. Co-culture system of NK cells with PC cells is used to test the ability of cancer cell proliferation, migration and invasion both in vitro and in vivo. And tail vein intravenous transfer was used to test metastasis in vivo. Meanwhile, extracellular vesicles (EVs) were separated and examined. Furthermore, reporter assay and Biotin-RNA pull down assay were performed to verify the interaction between molecules. NK cells can inhibit the malignant transformation of co-cultured PC cells both in vivo and in vitro , which requires miR-3607-3p. miR-3607-3p is found enriched in the EVs of NK cells and transmitted to PC cells, and low level of miR-3607-3p predicts poor prognosis in PC patients. It can also inhibit proliferation, migration and invasion of PC cells in vitro. Importantly, IL-26 is found to be a direct target of miR-3607-3p in PC cells. miR-3607-3p enriched in EVs derived from NK cells can inhibit the malignant transformation of PC probably through directly targeting of IL-26. [ABSTRACT FROM AUTHOR]

The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour-associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2-like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia-inducible factor-1α (HIF-1α), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase-9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF-1 and phosphorylated-signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2-like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF-1α and STAT3 signalling pathways. [ABSTRACT FROM AUTHOR]

The identification and characterization of long non‐coding RNAs (lncRNAs) in diverse biological process has currently developed rapidly. LncRNA‐PVT1, located adjacent to the MYC locus on chromosomal region 8q24, has been reported to be associated with many biological processes. However, the function and mechanism of PVT1 in pancreatic carcinoma (PC) is poorly understood. In this present study, we first measured the level of PVT1 in the PC cell lines and tissues by quantitative real‐time PCR (qRT‐PCR), and then employed loss‐of‐function and gain‐of‐function approaches to explore the association between PVT1 expression levels and PC cell proliferation/migration ability. Furthermore, bioinformatics analysis was utilized to show that PVT1 contains binding site for miR‐448 and an inverse correlation between PVT1 and miR‐448 was obtained in PC specimens. Additionally, dual luciferase reporter assay, RNA‐binding protein immunoprecipitation (RIP) and applied biotin‐avidin pulldown system were applied to further confirm that PVT1 directly bind with microRNA binding site harboring in the PVT1 sequence. Then, SERBP1 was identified as a target of miR‐448 according to the gene expression array analysis of PC clinical samples. Together, we revealed that PVT1 functions as an endogenous “sponge” by competing for miR‐448 binding to regulate the miRNA target SERBP1 and, therefore, promotes the proliferation and migration of PC cells. [ABSTRACT FROM AUTHOR]

Dermokine ( DMKN) was first identified in relation to skin lesion healing and skin carcinoma. Recently, its expression was associated with pancreatic cancer tumorigenesis, although its involvement remains poorly understood. Herein, we showed that DMKN loss of function in Patu-8988 and PANC-1 pancreatic cancer cell lines resulted in reduced phosphorylation of signal transducer and activator of transcription 3, and increased activation of ERK1/2 and AKT serine/threonine kinase. This decreased the proliferation ability of pancreatic ductal adenocarcinoma ( PDAC) cells. In addition, DMKN knockdown decreased the invasion and migration of PDAC cells, partially reversed the epithelial-mesenchymal transition, retarded tumor growth in a xenograft animal model by decreasing the density of microvessels, and attenuated the distant metastasis of human PDAC in a mouse model. Taken together, these data suggested that DMKN could be a potential prognostic biomarker and therapeutic target in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background/Aims: Pancreatic carcinoma (PC) is the one of the most common and malignant cancers worldwide. LncRNA taurine upregulated gene 1 (TUG1) was initially identified as a transcript upregulated by taurine, and the abnormal expression of TUG1 has been reported in many cancers. However, the biological role and molecular mechanism of TUG1 in PC still needs further investigation. Methods: Quantitative real-time PCR (qRT-PCR) was performed to measure the expression of TUG1 in PC cell lines and tissues. MTT and colony formation assays were used to measure the effect of TUG1 on cell proliferation. A wound healing assay, transwell assay and western blot assay were employed to determine the effect of TUG1 on cell migration and the epithelial mesenchymal transition (EMT) phenotype. RNA-binding protein immunoprecipitation (RIP) and a biotin-avidin pulldown system were performed to confirm the interaction between miR-328 and TUG1. A gene expression array analysis using clinical samples and RT-qPCR suggested that enhancer of zeste homolog 2 (EZH2) was a target of miR-382 in PC. Results: In this study, we reported that TUG1 was overexpressed in PC tissues and cell lines, and high expression of TUG1 predicted poor prognosis. Further experiments revealed that overexpressed TUG1 promoted cell proliferation, migration and contributed to EMT formation, whereas silenced TUG1 led to opposing results. Additionally, luciferase reporter assays, an RIP assay and an RNA-pulldown assay demonstrated that TUG1 could competitively sponge miR-382 and thereby regulate EZH2. Conclusion: Collectively, these findings revealed that TUG1 functions as an oncogenic lncRNA that promotes tumor progression, at least partially, by functioning as an endogenous 'sponge' and competing for miR-382 binding to the miRNA target EZH2. [ABSTRACT FROM AUTHOR]

α-solanine, a steroidal glycoalkaloid in potato, was found to have proliferation-inhibiting and apoptosis-promoting effect on multiple cancer cells, such as clone, liver, melanoma cancer cells. However, the antitumor efficacy of α-solanine on pancreatic cancer has not been fully evaluated. In this study, we inquired into the anti-carcinogenic effect of α-solanine against human pancreatic cancer cells. In the present study, we investigated the anti-carcinogenic effect of α-solanine against human pancreatic cancer cells. In vitro, α-solanine inhibited proliferation of PANC-1, sw1990, MIA PaCa-2 cells in a dose-dependent manner, as well as cell migration and invasion with atoxic doses. The expression of MMP-2/9, extracellular inducer of matrix metalloproteinase (EMMPRIN), CD44, eNOS and E-cadherin were suppressed by α-solanine in PANC-1 cells. Moreover, significantly decreased vascular endothelial growth factor (VEGF) expression and tube formation of endothelial cells were discerned following α-solanine treatment. Suppressed phosphorylation of Akt, mTOR, and Stat3, and strengthen phosphorylation of β-catenin was found, along with markedly decreased tran-nuclear of NF-κB, β-catenin and TCF-1. Following the administration of α-solanine (6 µg/g for 2 weeks) in xenograft model, tumor volume and weight were decreased by 61% and 43% (p<0.05) respectively, showing decreased MMP-2/9, PCNA and VEGF expression. In conclusion, α-solanine showed beneficial effects on pancreatic cancer in vitro and in vivo, which may via suppressing the pathway proliferation, angiogenesis and metastasis. [ABSTRACT FROM AUTHOR]

Abstract It is commonly recognized that aberrant expression of long non-coding RNAs (lncRNAs) is an important cause of cancer progression. The oncogenic property of KCNQ1OT1 has been identified in several malignant tumors. Here, we decided to explore the biological function and molecular mechanism of KCNQ1OT1 in cholangiocarcinoma (CCA). The expression conditions of KCNQ1OT1 in different tissues and cell lines were examined with qRT-PCR analysis. As expected, KCNQ1OT1 was highly expressed in CCA tissues and cell lines. Results of functional assays revealed the oncogenic function of KCNQ1OT in cholangiocarcinoma progression. The positive effect of KCNQ1OT1 on cell proliferation, invasion and epithelial-mesenchymal transition was identified by performing MTT assay, colony formation assay, transwell invasion assay and western blotting. Whereas, the negative effect of KCNQ1OT1 on the cell apoptosis was tested with flow cytometry analysis. Mechanism investigation revealed that KCNQ1OT1 can act as a ceRNA to improve CCA progression by regulating miR-140-5p/SOX4 axis. Recue assays were conducted to demonstrate the actual effects of KCNQ1OT1-miR-140-5p-SOX4 pathway on CCA progression. Highlights • Overexpressed KCNQ1OT1 is a prognostic factor for CCA patients. • The inhibitory effects of silenced KCNQ1OT1 on proliferation, EMT progress and invasion of CCA cells. • KCNQ1OT1 upregulates SOX4 through competitively binding with miR-140-5p. • KCNQ1OT1 improves CCA progression in a miR-140-5p/SOX4 dependent manner. [ABSTRACT FROM AUTHOR]

The onset, development, diagnosis, and treatment of cancer involve intricate interactions among various factors, spanning the realms of mechanics, physics, chemistry, and biology. Within our bodies, cells are subject to a variety of forces such as gravity, magnetism, tension, compression, shear stress, and biological static force/hydrostatic pressure. These forces are perceived by mechanoreceptors as mechanical signals, which are then transmitted to cells through a process known as mechanical transduction. During tumor development, invasion and metastasis, there are significant biomechanical influences on various aspects such as tumor angiogenesis, interactions between tumor cells and the extracellular matrix (ECM), interactions between tumor cells and other cells, and interactions between tumor cells and the circulatory system and vasculature. The tumor microenvironment comprises a complex interplay of cells, ECM and vasculature, with the ECM, comprising collagen, fibronectins, integrins, laminins and matrix metalloproteinases, acting as a critical mediator of mechanical properties and a key component within the mechanical signaling pathway. The vasculature exerts appropriate shear forces on tumor cells, enabling their escape from immune surveillance, facilitating their dissemination in the bloodstream, dictating the trajectory of circulating tumor cells (CTCs) and playing a pivotal role in regulating adhesion to the vessel wall. Tumor biomechanics plays a critical role in tumor progression and metastasis, as alterations in biomechanical properties throughout the malignant transformation process trigger a cascade of changes in cellular behavior and the tumor microenvironment, ultimately culminating in the malignant biological behavior of the tumor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bao, Kong, Ja, Wang, Qin, Sun and Dai.)

Transcriptome analysis is used to study gene expression in human tissues. It can promote the discovery of new therapeutic targets for related diseases by characterizing the endocrine function of pancreatic physiology and pathology, as well as the gene expression of pancreatic tumors. Compared to whole-tissue RNA sequencing, single-cell RNA sequencing (scRNA-seq) can detect transcriptional activity within a single cell. The scRNA-seq had an invaluable contribution to discovering previously unknown cell subtypes in normal and diseased pancreases, studying the functional role of rare islet cells, and studying various types of cells in diabetes as well as cancer. Here, we review the recent in vitro and in vivo advances in understanding the pancreatic physiology and pathology associated with single-cell sequencing technology, which may provide new insights into treatment strategy optimization for diabetes and pancreatic cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fu, Sun, Kong, Lou, Chen, Zhou, Huang, Qin, Shan and Dai.)

Diabetes mellitus (DM)-induced high blood sugar severely damages vascular endothelial cells (VECs), which are in direct contact with the blood. Diabetic complications cause difficulties in skin wound healing and VECs are important for this process. Previous studies demonstrated that high blood sugar delayed the repair of wounded VECs, but the underlying mechanism has remained elusive. To explore the effects of diabetic conditions on VEC damage, cells were incubated in a medium with high glucose and then subjected to RNA-sequencing based transcriptome analysis. The results revealed that numerous biological processes were altered by HG stress, including extracellular matrix-receptor interaction, NOD-like receptor signaling and the nuclear factor (NF)-κB pathway. HG treatment increased the levels of phosphorylated inhibitor of NF-κB (IκB-α), the key NF-κB signaling regulator as well as the transcripts of plasminogen activator inhibitor-1 and interleukin-8, two inflammatory response markers. Treatment with extracellular signal-regulated kinase (ERK)- and c-Jun N-terminal kinase (JNK)-specific inhibitors U0126 and sp600125, respectively, led to the activation of IκB-α; however, the inhibitor of IκBα phosphorylation Bay11-7082 did not affect ERK and JNK activity, suggesting that ERK/JNK signaling occurs upstream of NF-κB in VECs. The present study provided useful information regarding the effects of diabetes on VECs, which may provide approaches for therapies of diabetes-associated complications in the future.