scholarly journals Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed

2021 ◽  
pp. 1-17
Author(s):  
Breann C. Sommer ◽  
Deepika Dhawan ◽  
Audrey Ruple ◽  
José A. Ramos-Vara ◽  
Noah M. Hahn ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Cancer Progression ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Clinical Stage ◽  
Tumor Characteristics ◽  
Rna Seq ◽  
Advanced Clinical Stage ◽  
Naturally Occurring ◽  
Immune Signatures

BACKGROUND: Improved therapies are needed for patients with invasive urothelial carcinoma (InvUC). Tailoring treatment to molecular subtypes holds promise, but requires further study, including studies in pre-clinical animal models. Naturally-occurring canine InvUC harbors luminal and basal subtypes, mimicking those observed in humans, and could offer a relevant model for the disease in people. OBJECTIVE: To further validate the canine InvUC model, clinical and tumor characteristics associated with luminal and basal subtypes in dogs were determined, with comparison to findings from humans. METHODS: RNA sequencing (RNA-seq) analyses were performed on 56 canine InvUC tissues and bladder mucosa from four normal dogs. Data were aligned to CanFam 3.1, and differentially expressed genes identified. Data were interrogated with panels of genes defining luminal and basal subtypes, immune signatures, and other tumor features. Subject and tumor characteristics, and outcome data were obtained from medical records. RESULTS: Twenty-nine tumors were classified as luminal and 27 tumors as basal subtype. Basal tumors were strongly associated with immune infiltration (OR 52.22, 95%CI 4.68–582.38, P = 0.001) and cancer progression signatures in RNA-seq analyses, more advanced clinical stage, and earlier onset of distant metastases in exploratory analyses (P = 0.0113). Luminal tumors were strongly associated with breeds at high risk for InvUC (OR 0.06, 95%CI 0.01 –0.37, P = 0.002), non-immune infiltrative signatures, and less advanced clinical stage. CONCLUSIONS: Dogs with InvUC could provide a valuable model for testing new treatment strategies in the context of molecular subtype and immune status, and the search for germline variants impacting InvUC onset and subtype.

scholarly journals Activation of epithelial-mesenchymal transition process during breast cancer progression – the impact of molecular subtype and stromal composition

2021 ◽  
Author(s):  
Aleksandra Markiewicz ◽  
Justyna Topa ◽  
Marta Popęda ◽  
Jolanta Szade ◽  
Jarosław Skokowski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Nodes ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Ki 67 ◽  
Mesenchymal Transition ◽  
Metastatic Colonization ◽  
The Impact

Breast cancer (BC) is a heterogeneous disease with different molecular subtypes, which can be defined by oestrogen (ER), progesterone (PR) and human epidermal growth factor (HER2) receptors’ status as luminal, HER2+ and triple negative (TNBC). Molecular subtypes also differ in their epithelial-mesenchymal phenotype, which might be related to their aggressiveness, as activation of the epithelial-mesenchymal transition (EMT) is linked with increased ability of cancer cells to survive and metastasize. Nevertheless, the reverse process of mesenchymal-epithelial transition was shown to be required to sustain metastatic colonization. In this study we aimed to analyse activation of the EMT process in primary tumours (PT), which have (N+) or have not (N–) colonized the lymph nodes, as well as the lymph nodes metastases (LNM) themselves in 88 BC patients. We showed that luminal N– PT have the lowest activation of the EMT process (27%), in comparison to N+ PT (48%, p=0.06). On the other hand, TNBC do not show statistically significant EMT activation at the stage before lymph colonization (N–, 83%) and after colonization of the lymph nodes (N+, 63%, p=0.58). TNBC are also the least plastic (unable to change the EMT phenotype) in terms of turning EMT on or off between matched PT and LNM (0% EMT plasticity in TNBC vs 36% plasticity in luminal tumours). Moreover, in TNBC activation of EMT was correlated with increased cell division rate of the PT– in mesenchymal TNBC PT median Ki-67 was 45% in comparison to 10% in epithelial TNBC PT (p=0.002), whereas in PT of luminal subtypes Ki-67 did not differ between epithelial and mesenchymal phenotypes. Profiling of immunotranscriptome of epithelial and mesenchymal luminal BC with Nanostring technology revealed that N– PT with epithelial phenotype were enriched in inflammatory response signatures, whereas N+ mesenchymal cancers showed elevated MHC class II antigen presentation. Overall, activation of EMT changes during cancer progression and metastatic colonization of the lymph nodes depending on the PT molecular subtype and is related to differences in stromal signatures. Activation of EMT is associated with colonizing phenotype in luminal PT and proliferative phenotype of TNBC.

Evaluation of basal and luminal subtypes of urothelial carcinoma in African American and non-African American patients.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 305-305 ◽  
Author(s):  
Jordan Kardos ◽  
Jonathan J Melquist ◽  
David D. Chism ◽  
Woonyoung Choi ◽  
Katherine Cockerill ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
African American ◽  
Urothelial Carcinoma ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Tumor Stage ◽  
Intrinsic Subtype ◽  
Breast Cancer Patients ◽  
Muscle Invasive

305 Background: African American (AA) patients with urothelial carcinoma (UC) have been known to have a worse prognosis even when corrected for variables such as tumor stage and grade. Analysis of gene expression of several malignancies has resulted in the discovery of molecular subtypes with well-defined intrinsic biology. Recent studies in high grade (HG), muscle-invasive UC have led to the identification of two intrinsic, molecular subsets termed “luminal” and “basal” with characteristics of stages of urothelial differentiation, and that remarkably reflect the luminal and basal-like molecular subtypes of breast cancer. Patients with basal-like UC have a significantly worse overall survival. Methods: A total of 215 HG muscle-invasive UC tumors from the MDACC (n=75) and TCGA (n=140) were used to make intrinsic subtype calls using gene expression profiling (MDACC: DASL [cDNA-mediated Annealing, Selection, extension, and Ligation] and TCGA: RNA seq). Basal and luminal subtype calls were derived using previously published subtype classifiers (Damrauer et. al. PNAS, 2014 and Choi et. al. Cancer Cell, 2014). Patients were classified into AA and non-AA (white, Hispanic, or Asian) based upon self-reported race. Results: In total there were 16 and 199 tumors from AA and non-AA patients respectively. In non-AA patients, the proportion of tumors that were classified as basal and luminal were approximately equal (93 and 106 respectively), while in AA patients, there was enrichment of basal tumors (12 basal and 4 luminal) (p=0.03735, Fisher’s exact test). Conclusions: AA patients are enriched in the basal molecular subtype of UC. Similar findings have been previously documented in AA women with breast cancer. The enrichment of basal UC in AAs suggests that a biological explanation may in part underlie the poor outcomes seen in AA patients. Future studies will explore the prognostic and predictive implications of basal subtype in AA patients with UC.

Clear Cell Urothelial Carcinoma

2016 ◽  
Vol 25 (1) ◽  
pp. 18-25 ◽  
Author(s):  
Kien T. Mai ◽  
Justin Bateman ◽  
Bojana Djordjevic ◽  
Trevor A. Flood ◽  
Eric C. Belanger
Keyword(s):  
Urothelial Carcinoma ◽  
Clear Cell ◽  
Case Reports ◽  
Clinical Stage ◽  
Rapid Progression ◽  
Advanced Clinical Stage ◽  
Immunohistochemical Markers ◽  
Pax8 Expression ◽  
Muscle Invasion ◽  
Clear Cell Change

Clear cell urothelial carcinoma (CCUC) is a rare variant of urothelial carcinoma (UC) and its clinical significance has not been well elucidated. Consecutive cases of UC over a period of 5 years were reviewed. Histopathological tumor parameters, including the proportion of tumor cells with clear cell change, and patient outcomes were recorded. Expression of the following immunohistochemical markers was investigated: CK7, CK20, CK5, CD44, and PAX8. We also conducted a review of the literature for case reports/series of CCUC. Ten CCUCs were identified out of a total of 872 cases of UC. The clear cell component was characterized by prominent cytoplasmic membranes and voluminous clear cytoplasm, and accounted for 30% to 90% of the invasive tumor component. Of all the non-CCUC cases reviewed, at least 50% (noninvasive or invasive UC) showed focal areas of clear cell change that accounted for less than 5% of the neoplastic cells. Immunohistochemically, CCUC exhibited positive reactivity for CK5/CD44 (n = 9); CK20 (n = 5), PAX8 (very focal to extensive) (n = 6), and GATA3/CK7 (n = 10). Eight of 10 CCUC were of advanced clinical stage (pT3/pT4) and 6 of 10 experienced tumor recurrence and/or death due to disease. In conclusion, CCUC can be distinguished from non-CCUC by the extensive clear cell change in more than 30% of cells. This variant is associated with rapid progression to muscle invasion and metastasis, with an aggressive clinical course. Expression of CK5/CD44 may represent basal cell features in most CCUC cases, while PAX8 expression is suggestive of mesonephric derivation.

scholarly journals LncRNA LINC00152 promotes laryngeal cancer progression by sponging miR-613

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 240-248 ◽  
Author(s):  
Xuesong Zheng ◽  
Su Dong ◽  
Lele Sun ◽  
Jialu Xu ◽  
Jia Liu ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Clinical Stage ◽  
Cell Cancer ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Advanced Clinical Stage ◽  
Normal Tissues

AbstractBackgroundLong noncoding RNA (lncRNA) LINC00152 (CYTOR) has been reported to be upregulated and to serve as a diagnostic biomarker in multiple types of cancers, including laryngeal squamous cell cancer (LSCC). However, the functional role and molecular mechanisms of LINC00152 in LSCC progression need to be further investigated.MethodsLINC00152 levels in LSCC and adjacent normal tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Gene knockdown of LINC00152 was achieved in LSCC cells by use of small interfering RNA (siRNA). Cell proliferation, apoptosis, migration and invasion were examined by a series of methods. The micoRNA (miRNA) interaction with LINC00152 was screened by starBase v2.0 and confirmed by luciferase reporter activity.ResultsLINC00152 levels in LSCC tissues were significantly higher than those in adjacent normal tissue, and patients with lymph node metastasis or an advanced clinical stage displayed higher LINC00152 expression. Moreover, siRNA-mediated LINC00152 knockdown significantly inhibited the proliferation, migration and invasion of LSCC cells and induced apoptosis in those cells. Mechanistically, LINC00152 functioned as a competing endogenous RNA (ceRNA) sponging miR-613. The inhibitory effect of LINC00152 knockdown on malignant behavior was abrogated by inhibiting miR-613.ConclusionLINC00152 exerts an oncogenic effect on the tumorigenesis of LSCC by sponging miR-613 and may serve as a potential target for treating LSCC.

scholarly journals The long-noncoding RNA SOCS2-AS1 suppresses endometrial cancer progression by regulating AURKA degradation

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Fangfang Jian ◽  
Xiaoxia Che ◽  
Jingjing Zhang ◽  
Chang Liu ◽  
Gedan Liu ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Progression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Clinical Stage ◽  
Subcellular Location ◽  
Aurora Kinase ◽  
Advanced Clinical Stage ◽  
Cycle Arrest ◽  
Ubiquitin Proteasome

AbstractAberrant long-noncoding RNA (lncRNA) expression has been shown to be involved in the pathogenesis of endometrial cancer (EC). Herein, we report a novel tumor suppressor lncRNA SOCS2-AS1 in EC. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization and nuclear/cytoplasmic fractionation assays were used to detect the subcellular location. We found that SOCS2-AS1 was downregulated in EC tissues. Its reduced expression was correlated with advanced clinical stage and poor prognosis. Forced expression of SOCS2-AS1 suppressed EC cell proliferation and induced cell-cycle arrest and apoptosis. SOCS2-AS1-binding proteins were detected using RNA pull-down assay and mass spectrometry. Mechanistically, SOCS2-AS1 bound to Aurora kinase A (AURKA) and increased its degradation through the ubiquitin-proteasome pathway. In conclusion, SOCS2-AS1 may thus serve as a prognostic predictor and a biomarker for AURKA-inhibitor treatment in EC patients.

scholarly journals Interleukin-6 Differential Expression in Cancer Patients of Different Clinical Stages; a Possible Biomarker of Cancer Progression

2021 ◽  
Author(s):  
Abosede Obafunke Bello ◽  
John Abiodun Obadipe ◽  
Oluwabanke Temitope Adewusi ◽  
Anthony Oluwamuyiwa Ayanshina
Keyword(s):  
Cancer Patients ◽  
Differential Expression ◽  
Cancer Progression ◽  
Interleukin 6 ◽  
Clinical Stage ◽  
Stage Iv ◽  
Disease Stage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cancer Stage ◽  
Advanced Clinical Stage

Abstract PurposeThe study investigated interleukin-6 expression pattern across all stages of cancer. The research questions raised in the study were: Is there differential expression of Interleukin-6 across all cancer stages? and what relationship exists between serum interleukin-6 level and cancer stage?Methods The prospective case-control study comprised sixty two (62) purposively selected cancer participants across all stages and age range 18 years to 72years as well equal number of healthy volunteers from two medical centres in Nigeria. Three milliliters (3mls) of blood samples was collected intravenously from the participants and centrifuged after 30 minutes of collection at 3000rpm for 10 minutes to obtain serum. The serum level of Interleukin-6 was determined spectrophotometrically by Enzyme linked immunosorbent assay (ELISA). Data obtained were expressed as mean and standard error of the mean. One way Analysis of variance and t-test were employed to test for significance difference between the groups and the significant level was considered at P< 0.05. ResultsFindings from the study revealed significant (P< 0.05) higher mean serum interleukin-6 levels in stage IV cancer participants as compared to other disease stages. In the same way, significant higher mean Interleukin-6 level of stage III cancer participants as compared to that of stage I cancer participants was observed. Furthermore, the study revealed a significant correlation (P< 0.01) between serum Interleukin 6 concentration and cancer stage.Conclusion Serum interleukin-6 had differential expression in cancer patients at advanced clinical stage as compared to that of early disease stage.

Molecular Pathologic Subtyping of Urothelial Bladder Carcinoma in Young Patients

2019 ◽  
Vol 27 (5) ◽  
pp. 483-491
Author(s):  
Ksenya V. Shelekhova ◽  
Kirill A. Krykow ◽  
Igor A. Mescherjakov ◽  
Nikolay P. Mitin
Keyword(s):  
Urothelial Carcinoma ◽  
Bladder Carcinoma ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Young Patients ◽  
Case Series ◽  
Aberrant Expression ◽  
Free Survival ◽  
Urothelial Bladder Carcinoma ◽  
Muscle Invasive

Urothelial cancer is a heterogeneous disease with different molecular pathways that produce distinct molecular subtypes with specific characteristics and patient survival outcomes that require different therapeutic methods. Urothelial tumors in young patients appear to have distinct genetic features compared with their counterparts in older patients. Using a Lund subtype-specific immunohistochemistry panel, we performed molecular subtype profiling of an urothelial carcinoma case series (n = 49) in patients younger than 45 years of age. We demonstrate that the urothelial carcinoma in young patients tends to be of molecular urothelial-like A subtype (80%) and is associated with favorable, recurrent-free survival ( P = .022). In the urothelial-like cluster, we identified a portion of patients (10%) with high-grade non–muscle-invasive cancers (so-called urothelial-like D type) that showed significantly higher levels of squamous differentiation and p16, E2F3, and ki67 expression in addition to aberrant expression of Ck20 and a trend toward lower recurrent-free survival ( P = .057). Segregation of the cohort according to the decade of occurrence revealed that all tumors (n = 8) of patients younger than 30 years were clearly classified as urothelial-like A subtype. Statistically more aggressive molecular subtypes, such as urothelial-like D and basal/squamous-like (6%) subtypes, were identified in patients older than 30 years of age. Genomically unstable (2%) and mesenchymal-like (2%) subtypes were classified in the 40- to 44-year age group only. These data suggest that more aggressive molecular subtypes of bladder carcinoma appear and become more frequent with age. Further investigations are needed to validate this hypothesis.

scholarly journals Micro1278 Leads to Tumor Growth Arrest, Enhanced Sensitivity to Oxaliplatin and Vitamin D and Inhibits Metastasis via KIF5B, CYP24A1, and BTG2, Respectively

2021 ◽  
Vol 11 ◽  
Author(s):  
Weidong Lin ◽  
Heng Zou ◽  
Jinggang Mo ◽  
Chong Jin ◽  
Hao Jiang ◽  
...  
Keyword(s):  
Vitamin D ◽  
Tumor Growth ◽  
Clinical Stage ◽  
Growth Arrest ◽  
Clinical Samples ◽  
Cancer Type ◽  
Rna Seq ◽  
Loss Of Function ◽  
Advanced Clinical Stage ◽  
Chemotherapy Drugs

Colorectal cancer (CRC) is the most common cancer type in the digestive tract. Chemotherapy drugs, such as oxaliplatin, are frequently administered to CRC patients diagnosed with advanced or metastatic disease. A better understanding of the molecular mechanism underlying CRC tumorigenesis and the identification of optimal biomarkers for assessing chemotherapy sensitivity are essential for the treatment of CRC. Various microRNAs, constituting class of non-coding RNAs with 20-22 nucleotides, have served as oncogenes or tumor suppressors in CRC. We analyzed miR-1278 expression in clinical samples by qRT-PCR. We then explored the role of miR-1278 in CRC growth in vitro and in vivo as well as sensitivity to oxaliplatin via RNA-seq and gain- and loss-of-function assays. We found that miR-1278 was downregulated in CRC samples, correlating with advanced clinical stage, and overexpression of miR-1278 led to tumor growth arrest and increased sensitivity to oxaliplatin via enhanced apoptosis and DNA damage. Suppression of KIF5B by miR-1278 through direct binding to its 3′UTR was the mechanism for the miR-1278-mediated effects in CRC, miR-1278 inhibits metastasis of CRC through upregulation of BTG2. Additionally, we also found that the expression of CYP24A1, the main enzyme determining the biological half-life of calcitriol, was significantly inhibited by miR-1278, according to data from clinical, RNA-seq and functional assays, which allowed miR-1278 to sensitize CRC cells to vitamin D. In summary, our data demonstrated that miR-1278 may serve as a potential tumor suppressor gene and biomarker for determining sensitivity to oxaliplatin and vitamin D in CRC.

scholarly journals The relationship of tumor microenvironment and clinico-pathological parameters in different molecular subtypes of breast cancer

2021 ◽  
Author(s):  
Nina Čamdžić ◽  
Suada Kuskunović-Vlahovljak ◽  
Svjetlana Radović ◽  
Mirsad Dorić ◽  
Mirsad Babić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Tumor Stroma ◽  
Histologic Grade ◽  
Clinicopathological Parameters ◽  
Immunohistochemical Expression ◽  
Ki 67

Introduction: Tumor microenvironment plays a significant role in tumor progression. Tumor stroma is one of the strongest modifiers of tumor cell response, cancer behavior, and cancer progression. This study aimed to investigate the correlation of matrix metalloproteinase-9 (MMP-9) expression and tumor-stroma ratio (TSR) with standard clinicopathological parameters in different molecular subtypes of breast cancer.Methods: Ninety biopsy samples of primary breast cancer diagnosed at the Department of Pathology, School of Medicine, Sarajevo, were selected for this study. The molecular subtype was determined based on the immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. Stromal and tumoral MMP-9 immunohistochemical expression and the TSR were determined for each tumor.Results: Tumoral MMP-9 expression correlated positively with the presence of lymphovascular invasion (p= 0.016). TSR showed significant association and correlation with tumor grade (G) (p= 0.031; p= 0.049) and tumor size (pT) (p = 0.049;p= 0.021, respectively). Stromal MMP-9 expression correlated with histologic type, histologic grade of tumor, and lymphocytic inflammatory infiltrate (p= 0.021;p= 0.047, p= 0.038, respectively). A higher percentage of stromal MMP-9 expression correlated with the strongest lymphocytic response (p = 0.007). Significant correlation was observed between molecular subtypes and histologic grade of the tumor (p= 0.032).Conclusion: Our results, to some extent, confirm the significance of the tumor microenvironment in breast cancer, especially when it is about stromal MMP-9 expression. Although we observed significant association, without linear correlation, we found no significant correlation between molecular subtypes of breast cancer and MMP-9 expression.

scholarly journals Long Noncoding RNASBF2-AS1 Promotes Gastric Cancer Progression via Regulating miR-545/EMS1 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Mingyuan He ◽  
Li Feng ◽  
Lingzhi Qi ◽  
Min Rao ◽  
Yonggang Zhu
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Clinical Stage ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Luciferase Reporter Gene ◽  
Advanced Clinical Stage ◽  
Gene Assay

Objective. Long noncoding RNA (LncRNA) SBF2-AS1 was reportedly to function as an oncogene in several types of cancers, such as hepatocellular carcinoma, nonsmall cell lung cancer, glioma, and colorectal cancer. However, the biological roles and regulatory mechanisms of SBF2-AS1 in gastric cancer (GC) are unknown. Methods. The expression of SBF2-AS1 and miR-545 were examined in GC tissues and cell lines via real-time quantitative PCR. The relationship of SBF2-AS1 with miR-545 was verified via dual-luciferase reporter gene assay and RNA immunoprecipitation. The influences of SBF2-AS1 on cell proliferation, migration, and invasion were determined using cell counting Kit-8 (CCK-8), wound healing, and transwell invasion assays, respectively. Results. LncRNA SBF2-AS1 expression was upregulated in GC tissues, especially in advanced clinical stage cases. Moreover, increased SBF2-AS1 indicated a poor survival rate. Functionally, the downregulation of SBF2-AS1 by siRNA in GC cells suppressed the proliferation, migration, and invasion. In terms of mechanism, SBF2-AS1 can directly bind to miR-545 and regulate its expression. Moreover, SBF2-AS1 knockdown significantly decreased the expression of EMS1, which was the direct target of miR-545. Importantly, inhibition of miR-545 or overexpression of EMS1 partially reversed SBF2-AS1-depletion-caused suppression on proliferation, migration, and invasion. Conclusion. These findings elucidated a crucial role of SBF2-AS1 as a miR-545 sponge in GC cells, suggesting that SBF2-AS1 might be a potential target for GC.

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