Molecular characterization of pancreatic cancers as seen in the SLUG gene revealing cancer progression.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 433-433 ◽  
Author(s):  
Natsuko Kawanishi ◽  
Yasmine Baca ◽  
Joanne Xiu ◽  
Hiroyuki Arai ◽  
Jingyan Wang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cell ◽  
Pancreatic Tumors ◽  
Therapeutic Effects ◽  
Expression Levels ◽  
Functional Roles ◽  
Genome Medicine ◽  
Whole Transcriptome Sequencing ◽  
Slug Expression ◽  
Tumor Mutational Burden

433 Background: The SLUG gene plays an important role in EMT by repressing E-cadherin and promotes metastasis. Previous data suggest that overexpressed SLUG gene in pancreatic cancer (PC) showing a high frequency of metastasis and poor prognosis. As SLUG contribution to characteristics or metastatic features remains elusive, we clarified its functional roles in PC progression. Methods: A total of 2958 pancreatic tumors were analyzed using Whole Transcriptome sequencing, NextGen Sequencing (NGS) (NextSeq, 592 gene panel) or Whole Exome Sequencing (WES) (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Microsatellite instability (MSI) status was tested by fragment analysis, immunohistochemistry (IHC) and NGS. PD-L1 expression was tested by IHC. Tumor mutational burden (TMB) was measured by counting all mutations found per tumor (a universal cutoff point of ≧10 mutations per MB). Immune cell fraction was calculated by quanTIseq (Finotello 2019, Genome Medicine). Results: A total of 1274 primary and 1684 metastatic pancreatic tumors were included for this study. They were divided equally into four classes in each group, according to their SLUG expression levels. Tumors in the highest quartile of SLUG expression (QH) showed significantly higher frequency in peritoneal-retroperitoneal-omentum metastasis (15.0%) compared to the lowest quartile (QL) (4.8%) (p = .0001). Similar trends were seen in the abdomen (6% vs 1%, p = .001) and bone (2.8% vs 0.0%, p = .005). However, liver (55.0% in QH vs 63.1% in QL) and lung (2.8% vs 14.1%) metastasis occurred most frequently in QL and the least frequently in QH (p = .0197 and p = .001, respectively). This data indicated that tumors with high SLUG gene expression levels tend to lead to disseminated metastasis, and with low expression levels, they tend to spread intravascularly. We detected significant differences among genetic mutations in ATM (5.7% in QL vs 1.8% in QH, p < 0.001) and APC (2.9% vs 0.5%, p < 0.001), and Wnt signaling expressions were higher in QL (4.6%) than QH (0.7%) (p < 0.001). Binary TMB-H and MSI-H tumors had higher frequencies in QL (2.7% and 2.1%) compared to QH (0.3% and 0.1%) (p < 0.001 in both). Contrastingly, PD-L1 expression levels were higher in QH (23.4%) compared to QL (11.0%) (p < 0.001) and had a linear relationship with the expression levels. The median values of the population of B cells, M1 and M2 macrophages were significantly higher in QH compared to QL, but those of myeloid dendritic and CD8+T cells conversely decrease as the SLUG expression increases. Conclusions: Our data indicated the SLUG expression level could determine the tumor characteristics in progression, especially the pattern of metastasis in PC, and it could possibly predict the prognosis and/or therapeutic effects. We also showed immune oncologic markers which have some relationships with SLUG expressions. Further investigation is warranted to better understand SLUG gene functions.

scholarly journals Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 207 ◽  
Author(s):  
Emily Rodrigues ◽  
Matthew Macauley
Keyword(s):  
Sialic Acid ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Immune Cell ◽  
Cell Types ◽  
Functional Roles ◽  
Cell Responses ◽  
Disease Prognosis ◽  
Sialic Acid Binding ◽  
Cancer Types

Cell surface glycosylation is dynamic and often changes in response to cellular differentiation under physiological or pathophysiological conditions. Altered glycosylation on cancers cells is gaining attention due its wide-spread occurrence across a variety of cancer types and recent studies that have documented functional roles for aberrant glycosylation in driving cancer progression at various stages. One change in glycosylation that can correlate with cancer stage and disease prognosis is hypersialylation. Increased levels of sialic acid are pervasive in cancer and a growing body of evidence demonstrates how hypersialylation is advantageous to cancer cells, particularly from the perspective of modulating immune cell responses. Sialic acid-binding receptors, such as Siglecs and Selectins, are well-positioned to be exploited by cancer hypersialylation. Evidence is also mounting that Siglecs modulate key immune cell types in the tumor microenvironment, particularly those responsible for maintaining the appropriate inflammatory environment. From these studies have come new and innovative ways to block the effects of hypersialylation by directly reducing sialic acid on cancer cells or blocking interactions between sialic acid and Siglecs or Selectins. Here we review recent works examining how cancer cells become hypersialylated, how hypersialylation benefits cancer cells and tumors, and proposed therapies to abrogate hypersialylation of cancer.

scholarly journals Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

2019 ◽  
Vol 9 (22) ◽  
pp. 4784
Author(s):  
Vietsch ◽  
Peran ◽  
Suker ◽  
van den Bosch ◽  
Sijde ◽  
...  
Keyword(s):  
Cancer Progression ◽  
B Lymphocyte ◽  
Immune Cell ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Tumor Stroma ◽  
Recurrence Risk ◽  
High Serum ◽  
Ductal Adenocarcinoma ◽  
Before And After

Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic KrasG12D/+; Trp53R172H/+; P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated ≥3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.

scholarly journals The Role of Cancer-Associated Fibroblasts in Tumor Progression

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1399
Author(s):  
Rushikesh S. Joshi ◽  
Samanvi S. Kanugula ◽  
Sweta Sudhir ◽  
Matheus P. Pereira ◽  
Saket Jain ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Immune Cell ◽  
Systemic Disease ◽  
Genomic Medicine ◽  
Therapeutic Targets ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancers

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

scholarly journals Echinacoside exerts anti-tumor activity via the miR-503-3p/TGF-β1/Smad aixs in liver cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wen Li ◽  
Jing Zhou ◽  
Yajie Zhang ◽  
Jing Zhang ◽  
Xue Li ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Cancer Cells ◽  
Hepg2 Cells ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Expression Levels ◽  
Liver Cancer Cells ◽  
Anti Tumor Activity ◽  
Tgf Β1

Abstract Background Echinacoside (ECH) is the main active ingredient of Cistanches Herba, which is known to have therapeutic effects on metastatic tumors. However, the effects of ECH on liver cancer are still unclear. This study was to investigate the effects of ECH on the aggression of liver cancer cells. Methods Two types of liver cancer cells Huh7 and HepG2 were treated with different doses of ECH at different times and gradients. MTT and colony formation assays were used to determine the effects of ECH on the viability of Huh7 and HepG2 cells. Transwell assays and flow cytometry assays were used to detect the effects of ECH treatment on the invasion, migration, apoptosis and cell cycle of Huh7 and HepG2 cells. Western blot analysis was used to detect the effects of ECH on the expression levels of TGF-β1, smad3, smad7, apoptosis-related proteins (Caspase-3, Caspase-8), and Cyto C in liver cancer cells. The relationship between miR-503-3p and TGF-β1 was detected using bioinformatics analysis and Luciferase reporter assay. Results The results showed that ECH inhibited the proliferation, invasion and migration of Huh7 and HepG2 cells in a dose- and time-dependent manner. Moreover, we found that ECH caused Huh7 and HepG2 cell apoptosis by blocking cells in S phase. Furthermore, the expression of miR-503-3p was found to be reduced in liver tumor tissues, but ECH treatment increased the expression of miR-503-3p in Huh7 and HepG2 cells. In addition, we found that TGF-β1 was identified as a potential target of miR-503-3p. ECH promoted the activation of the TGF-β1/Smad signaling pathway and increased the expression levels of Bax/Bcl-2. Moreover, ECH could trigger the release of mitochondrial Cyto C, and cause the reaction Caspases grade. Conclusions This study demonstrates that ECH exerts anti-tumor activity via the miR-503-3p/TGF-β1/Smad aixs in liver cancer, and provides a safe and effective anti-tumor agent for liver cancer.

scholarly journals SAT0007 BLOCKING HISTAMINE-RELEASING FACTOR/TRANSLATIONALLY CONTROLLED TUMOR PROTEIN (HRF/TCTP) ATTENUATES AGGRESSIVENESS OF FIBROBLAST-LIKE SYNOVIOCYTES AND AMELIORATES COLLAGEN-INDUCED ARTHRITIS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 934.3-934
Author(s):  
M. Kim ◽  
Y. Choe ◽  
H. Lee ◽  
Y. H. Cheon ◽  
S. I. Lee
Keyword(s):  
Rheumatoid Arthritis ◽  
Cancer Progression ◽  
Inflammatory Responses ◽  
Joint Destruction ◽  
Serum Levels ◽  
Therapeutic Effects ◽  
Collagen Induced Arthritis ◽  
Translationally Controlled Tumor Protein ◽  
Biochemical Analyses ◽  
Fibroblast Like Synoviocytes

Background:Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses. Increased expression of HRF/TCTP occurs in joints of rheumatoid arthritis (RA) patients, but the role of HRF/TCTP in RA remains undefinedObjectives:In this study, we explored the pathogenic significance of HRF/TCTP and evaluated therapeutic effects of HRF/TCTP blockade in RA.Methods:HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine experimental phenotypes of RA. HRF/TCTP levels were measured in sera and joint fluids in patients with RA and compared to those with osteoarthritis, ankylosing spondylitis, Behcet disease, and healthy controls. HRF/TCTP expression was also assessed in synovium and fibroblast-like synoviocytes (FLS) obtained from RA or OA patients. Finally, we assessed effects of HRF/TCTP and dimerized HRF/TCTP binding peptide-2 (dTBP2), an inhibitor of HRF/TCTP, in RA-FLS and CIA mice.Results:Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice, and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels were higher in sera, synovial fluid, synovium, and FLS of patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with disease activity in RA. Tumor-like aggressiveness of RA-FLS was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice, and had no detrimental effect in a murine tuberculosis model.Conclusion:Our results indicate that HRF/TCTP represents a novel biomarker and therapeutic target for diagnosis and treatment of RA.References:N/AAcknowledgments :National Research Foundation of KoreaKorea Health Industry Development InstituteDisclosure of Interests:None declared

scholarly journals Antifungal Effect of Long Noncoding RNA 9708-1 in the Vulvovaginal Candidiasis Murine Model

2021 ◽  
Vol 186 (2) ◽  
pp. 177-188
Author(s):  
Ying Wu ◽  
Lisha Jiang ◽  
Lingling Zhang ◽  
Xia Liu ◽  
Lina Yan ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Basal Layer ◽  
Vulvovaginal Candidiasis ◽  
Control Group ◽  
Therapeutic Effects ◽  
Blank Control Group ◽  
Candida Spp ◽  
Expression Levels ◽  
Gene And Protein Expression

AbstractVulvovaginal candidiasis (VVC) caused by Candida spp. affects 70–75% of women at least once during their lives. We aim to elucidate the potential mechanism of VVC and investigate the therapeutic effects of long noncoding RNA 9708-1. Female BALB/c mice were randomized to four treatment groups, including the blank control group, VVC control group, vehicle control group and lncRNA 9708-1-overexpressed group. Mice were euthanized on Day 4, Day 7 and Day 14 after treatment. Colony-forming unit (CFU) was measured, and the inflammation was detected by hematoxylin and eosin (H&E). Gene and protein expression levels of lncRNA 9708-1 and FAK were determined by real-time PCR, Western blot and immunohistochemistry. The overexpression of lncRNA 9708-1 significantly decreased the fungal load from Day 4 to 7. H&E staining indicated that the impaired histological profiles were improved in lncRNA 9708-1-overexpressed group. LncRNA 9708-1 led to a significant increase in FAK level of vagina tissue which is expressed mainly in epithelial basal layer. This study suggests that lncRNA 9708-1 played a protective role on murine experimental VVC by upregulating the expression levels of FAK.

scholarly journals Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 302 ◽  
Author(s):  
Xin Zhang ◽  
Yao Qin ◽  
Zhaohai Pan ◽  
Minjing Li ◽  
Xiaona Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Protein Expression ◽  
Cell Cycle Arrest ◽  
Phase Cell ◽  
G1 Phase ◽  
Therapeutic Effects ◽  
Human Gastric Cancer ◽  
Expression Levels ◽  
Cycle Arrest

The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties. The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells. We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells. Further investigation showed that CBD significantly upregulated ataxia telangiectasia-mutated gene (ATM) and p53 protein expression and downregulated p21 protein expression in SGC-7901 cells, which subsequently inhibited the levels of CDK2 and cyclin E, thereby resulting in cell cycle arrest at the G0–G1 phase. In addition, CBD significantly increased Bax expression levels, decreased Bcl-2 expression levels and mitochondrial membrane potential, and then upregulated the levels of cleaved caspase-3 and cleaved caspase-9, thereby inducing apoptosis in SGC-7901 cells. Finally, we found that intracellular reactive oxygen species (ROS) increased after CBD treatment. These results indicated that CBD could induce G0–G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.

scholarly journals Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Haoting Sun ◽  
Chaoqun Wang ◽  
Beiyuan Hu ◽  
Xiaomei Gao ◽  
Tiantian Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Tumor Metastasis ◽  
Metastatic Potential ◽  
Functional Roles ◽  
Stat3 Phosphorylation ◽  
Hcc Cells

AbstractIntercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.

scholarly journals YWHAZ interacts with DAAM1 to promote cell migration in breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jie Mei ◽  
Yan Liu ◽  
Xinqian Yu ◽  
Leiyu Hao ◽  
Tao Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Transcriptional Regulator ◽  
Expression Levels ◽  
Functional Roles ◽  
Normal Tissues ◽  
Rhoa Activation ◽  
Promote Cell Migration

AbstractDishevelled-associated activator of morphogenesis 1 (DAAM1) is a critical driver in facilitating metastasis in breast cancer (BrCa). However, molecular mechanisms for the regulation of DAAM1 activation are only partially elucidated. In this research, the expression levels of YWHAZ and DAAM1 were examined by immunohistochemistry (IHC) staining in BrCa tissues. The functional roles of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ)–DAAM1 axis and their regulator microRNA-613 (miR-613) in BrCa cells and associated molecular mechanisms were demonstrated in vitro. As results, the expression levels of DAAM1 and YWHAZ were significantly upregulated in BrCa tissues compared with normal tissues and remarkably associated with poor prognosis. Besides, DAAM1 and YWHAZ were positively correlated with each other in BrCa tissues. YWHAZ interacted and colocalized with DAAM1 in BrCa cells, which was essential for DAAM1-mediated microfilament remodeling and RhoA activation. Moreover, miR-613 directly targeted both YWHAZ and DAAM1, contributing to inhibiting BrCa cells migration via blocking the complex of YWHAZ–DAAM1. To sum up, these data reveal that YWHAZ regulates DAAM1 activation, and the YWHAZ–DAAM1 complex is directly targeted by the shared post-transcriptional regulator miR-613.

scholarly journals Immunometabolic Status of COVID-19 Cancer Patients

2020 ◽  
Vol 100 (4) ◽  
pp. 1839-1850
Author(s):  
A. Sica ◽  
M. P. Colombo ◽  
A. Trama ◽  
L. Horn ◽  
M. C. Garassino ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Cancer Progression ◽  
Macrophage Activation ◽  
Viral Infections ◽  
Immune Cell ◽  
Case Series ◽  
The United States ◽  
Alternative Activation ◽  
Nad Metabolism ◽  
Increased Risk

Cancer patients appear to be more likely to be diagnosed with coronavirus disease 2019 (COVID-19). This is supported by the understanding of immunometabolic pathways that intersect patients with infection and cancer. However, data derived by case series and retrospective studies do not offer a coherent interpretation, since data from China suggest an increased risk of COVID-19, while data from the United States and Italy show a prevalence of COVID-19 in cancer patients comparable with the general population. Noteworthy, cancer and COVID-19 exploit distinct patterns of macrophage activation that promote disease progression in the most severe forms. In particular, the alternative activation of M2-polarized macrophages plays a crucial role in cancer progression. In contrast, the macrophage-activation syndrome appears as the source of M1-related cytokine storm in severe COVID-19 disease, thus indicating macrophages as a source of distinct inflammatory states in the two diseases, nonetheless as a common therapeutic target. New evidence indicates that NAMPT/NAD metabolism can direct both innate immune cell effector functions and the homeostatic robustness, in both cancer and infection. Moreover, a bidirectional relationship exists between the metabolism of NAD and the protective role that angiotensin converting enzyme 2, the COVID-19 receptor, can play against hyperinflammation. Within this immunometabolic framework, the review considers possible interference mechanisms that viral infections and tumors elicit on therapies and provides an overview for the management of patients with cancer affected by COVID-19, particularly for the balance of risk and benefit when planning normally routine cancer treatments and follow-up appointments.

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