Publications by authors named "Martin Pichler"

248 Publications

MicroRNA expression profiling with a Droplet Digital PCR assay enables molecular diagnosis and prognosis of cancers of unknown primary (CUPs).

Mol Oncol 2021 Jun 2. Epub 2021 Jun 2.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Metastasis is responsible for the majority of cancer-related deaths. Particularly challenging is the management of metastatic cancer of unknown primary site (CUP), whose tissue of origin (TOO) remains undetermined even after extensive investigations and whose therapy is rather unspecific and poorly effective. Molecular approaches to identify the most probable TOO of CUPs can overcome some of these issues. In this study, we applied a pre-determined set of 89 microRNAs (miRNAs) to infer the TOO of 53 metastatic cancers of unknown or uncertain origin. The miRNA expression was assessed with Droplet Digital PCR in 159 samples, including primary tumors from 17 tumor classes (reference set), and metastases of known and unknown origin (test set). We combined two different statistical models for class prediction to obtain the most probable TOOs: the nearest shrunken centroids approach of Prediction Analysis of Microarrays (PAMR) and the Least Absolute Shrinkage and Selection Operator (LASSO) models. The molecular test was successful for all formalin-fixed paraffin-embedded samples and provided a TOO identification within 1 week from the biopsy procedure. The most frequently predicted origins were gastrointestinal, pancreas, breast, lung and bile duct. The assay was applied also to multiple metastases from the same CUP, collected from different metastatic sites: the predictions showed a strong agreement, intrinsically validating our assay. The final CUPs' TOO prediction was compared with the clinico-pathological hypothesis of primary site. Moreover, a panel of 13 miRNAs proved to have prognostic value and be associated with overall survival in CUP patients. Our study demonstrated that miRNA expression profiling in CUP samples could be employed as diagnostic and prognostic test. Our molecular analysis can be performed on request, concomitantly with standard diagnostic workup and in association with genetic profiling, to offer valuable indications about the possible primary site, thereby supporting treatment decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.13026DOI Listing
June 2021

Gemcitabine/nab-Paclitaxel versus FOLFIRINOX for palliative first-line treatment of advanced pancreatic cancer: A propensity score analysis.

Eur J Cancer 2021 Jul 2;151:3-13. Epub 2021 May 2.

Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed.

Methods: We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX.

Results: In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329).

Conclusion: This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.03.040DOI Listing
July 2021

Influence of tumor-infiltrating immune cells on local control rate, distant metastasis, and survival in patients with soft tissue sarcoma.

Oncoimmunology 2021 Mar 11;10(1):1896658. Epub 2021 Mar 11.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.

Soft tissue sarcomas (STS) are considered non-immunogenic, although distinct entities respond to anti-tumor agents targeting the tumor microenvironment. This study's aims were to investigate relationships between tumor-infiltrating immune cells and patient/tumor-related factors, and assess their prognostic value for local recurrence (LR), distant metastasis (DM), and overall survival (OS). One-hundred-eighty-eight STS-patients (87 females [46.3%]; median age: 62.5 years) were retrospectively analyzed. Tissue microarrays (in total 1266 cores) were stained with multiplex immunohistochemistry and analyzed with multispectral imaging. Seven cell types were differentiated depending on marker profiles (CD3+, CD3+ CD4+ helper, CD3+ CD8+ cytotoxic, CD3+ CD4+ CD45RO+ helper memory, CD3+ CD8+ CD45RO+ cytotoxic memory T-cells; CD20 + B-cells; CD68+ macrophages). Correlations between phenotype abundance and variables were analyzed. Uni- and multivariate Fine&Gray and Cox-regression models were constructed to investigate prognostic variables. Model calibration was assessed with C-index. IHC-findings were validated with TCGA-SARC gene expression data of genes specific for macrophages, T- and B-cells. B-cell percentage was lower in patients older than 62.5 years ( = .013), whilst macrophage percentage was higher ( = .002). High B-cell ( = .035) and macrophage levels ( = .003) were associated with increased LR-risk in the univariate analysis. In the multivariate setting, high macrophage levels ( = .014) were associated with increased LR-risk, irrespective of margins, age, gender or B-cells. Other immune cells were not associated with outcome events. High macrophage levels were a poor prognostic factor for LR, irrespective of margins, B-cells, gender and age. Thus, anti-tumor, macrophage-targeting agents may be applied more frequently in tumors with enhanced macrophage infiltration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2021.1896658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954425PMC
March 2021

Profiling of circulating tumor DNA and tumor tissue for treatment selection in patients with advanced and refractory carcinoma: a prospective, two-stage phase II Individualized Cancer Treatment trial.

Ther Adv Med Oncol 2021 27;13:1758835920987658. Epub 2021 Feb 27.

Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma.

Patients And Methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases the CureMatch PreciGENE™ decision support algorithm.

Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8-71.0] compared with 81.5 days (IQR 68.5-117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6-0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option.

Conclusions: Our study employed a histotype-agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EudraCT: 2014-005341-44.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1758835920987658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923987PMC
February 2021

Involvement of Long Non-Coding RNAs in Glucose Metabolism in Cancer.

Cancers (Basel) 2021 Feb 26;13(5). Epub 2021 Feb 26.

Research Unit of Non-Coding RNAs and Genome Editing, Division of Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria.

The rapid and uncontrolled proliferation of cancer cells is supported by metabolic reprogramming. Altered glucose metabolism supports cancer growth and progression. Compared with normal cells, cancer cells show increased glucose uptake, aerobic glycolysis and lactate production. Byproducts of adjusted glucose metabolism provide additional benefits supporting hallmark capabilities of cancer cells. Long non-coding RNAs (lncRNAs) are a heterogeneous group of transcripts of more than 200 nucleotides in length. They regulate numerous cellular processes, primarily through physical interaction with other molecules. Dysregulated lncRNAs are involved in all hallmarks of cancer including metabolic alterations. They may upregulate metabolic enzymes, modulate the expression of oncogenic or tumor-suppressive genes and disturb metabolic signaling pathways favoring cancer progression. Thus, lncRNAs are not only potential clinical biomarkers for cancer diagnostics and prediction but also possible therapeutic targets. This review summarizes the lncRNAs involved in cancer glucose metabolism and highlights their underlying molecular mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13050977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956509PMC
February 2021

Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer.

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13040699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915291PMC
February 2021

Cancer of Unknown Primary: Challenges and Progress in Clinical Management.

Cancers (Basel) 2021 Jan 25;13(3). Epub 2021 Jan 25.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy.

Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of unknown primary (CUP). Accounting for approximately 3-5% of all cancer diagnoses, CUPs are characterized by an aggressive clinical behavior and represent a real therapeutic challenge. The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. In the era of precision medicine, it is essential to characterize CUP molecular features, including the expression profile of non-coding RNAs, to improve our understanding of CUP biology and identify novel therapeutic strategies. This review article sheds light on this enigmatic disease by summarizing the current knowledge on CUPs focusing on recent discoveries and emerging diagnostic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13030451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866161PMC
January 2021

The AST/ALT Ratio Is an Independent Prognostic Marker for Disease-free Survival in Stage II and III Colorectal Carcinoma.

Anticancer Res 2021 Jan;41(1):429-436

Division of Oncology, Department of Internal Medicine, Graz, Austria.

Background/aim: The Aspartate aminotransaminase/Alanine aminotransaminase ratio (AST/ALT ratio) has been identified as a prognostic marker for several malignancies. In this study, we evaluated the prognostic value of the AST/ALT ratio in a large cohort of non-metastatic colorectal cancer patients (CRC).

Patients And Methods: A total of 536 patients with stage II and III CRC, as well as available AST/ALT ratio were included in this single-center retrospective analysis. Laboratory data were measured within two weeks before histological tumor diagnosis. Co-Primary endpoints for this analysis were disease-free survival (DFS) and overall survival (OS).

Results: In univariate cox regression DFS was significantly shorter in patients with an elevated AST/ALT ratio (HR=1.568, 95%CI=1.10-2.23, p=0.012). In multivariable analysis, the prognostic association between an elevated AST/ALT ratio and a poor survival prevailed statistically significant (HR=1.53, 95%C=1.05-2.22, p=0.026). No statistically significant association between the AST/ALT ratio and OS was observed (HR=1.4, 95% CI=0.89-2.22, p=0.14).

Conclusion: In this study, the serum AST/ALT ratio emerged as a valid prognostic marker for DFS in non-metastatic colorectal cancer patients at stage II and III.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14792DOI Listing
January 2021

Micro-RNA-125a mediates the effects of hypomethylating agents in chronic myelomonocytic leukemia.

Clin Epigenetics 2021 Jan 6;13(1). Epub 2021 Jan 6.

Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, 8036, Graz, Austria.

Background: Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic malignancy that arises from hematopoietic stem and progenitor cells (HSPCs). Patients with CMML are frequently treated with epigenetic therapeutic approaches, in particular the hypomethylating agents (HMAs), azacitidine (Aza) and decitabine (Dec). Although HMAs are believed to mediate their efficacy via re-expression of hypermethylated tumor suppressors, knowledge about relevant HMA targets is scarce. As silencing of tumor-suppressive micro-RNAs (miRs) by promoter hypermethylation is a crucial step in malignant transformation, we asked for a role of miRs in HMA efficacy in CMML.

Results: Initially, we performed genome-wide miR-expression profiling in a Kras-induced CMML mouse model. Selected candidates with prominently decreased expression were validated by qPCR in CMML mice and human CMML patients. These experiments revealed the consistent decrease in miR-125a, a miR with previously described tumor-suppressive function in myeloid neoplasias. Furthermore, we show that miR-125a downregulation is caused by hypermethylation of its upstream region and can be reversed by HMA treatment. By employing both lentiviral and CRISPR/Cas9-based miR-125a modification, we demonstrate that HMA-induced miR-125a upregulation indeed contributes to mediating the anti-leukemic effects of these drugs. These data were validated in a clinical context, as miR-125a expression increased after HMA treatment in CMML patients, a phenomenon that was particularly pronounced in cases showing clinical response to these drugs.

Conclusions: Taken together, we report decreased expression of miR-125a in CMML and delineate its relevance as mediator of HMA efficacy within this neoplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00979-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789782PMC
January 2021

Role of non-coding RNAs in modulating the response of cancer cells to paclitaxel treatment.

Biomed Pharmacother 2021 Feb 24;134:111172. Epub 2020 Dec 24.

Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Paclitaxel is a chemotherapeutic substance that is administered for treatment of an extensive spectrum of human malignancies. In spite of its potent short-term effects against tumor cells, resistance to paclitaxel occurs in a number of patients precluding its long-term application in these patients. Non-coding RNAs have been shown to influence response of cancer cells to this chemotherapeutic agent via different mechanisms. Mechanistically, these transcripts regulate expression of several genes particularly those being involved in the apoptotic processes. Lots of in vivo and in vitro assays have demonstrated the efficacy of oligonucleotide-mediated microRNAs (miRNA)/ long non-coding RNAs (lncRNA) silencing in enhancement of response of cancer cells to paclitaxel. Therefore, targeted therapies against non-coding RNAs have been suggested as applicable modalities for combatting resistance to this agent. In the present review, we provide a summary of studies which assessed the role of miRNAs and lncRNAs in conferring resistance to paclitaxel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2020.111172DOI Listing
February 2021

Deficiency of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis.

Cancer Metab 2020 Nov 26;8(1):26. Epub 2020 Nov 26.

Institute of Biochemistry, Graz University of Technology, Humboldtstrasse 46/III, 8010, Graz, Austria.

Background: Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo. However, the impact of intracellular aspartate levels on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.

Results: Low AGC1 expression correlates with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells.

Conclusion: This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation, do not always reflect metastatic capacity in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40170-020-00232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690131PMC
November 2020

Non-Coding RNAs and SARS-Related Coronaviruses.

Viruses 2020 12 1;12(12). Epub 2020 Dec 1.

Comprehensive Cancer Center Graz, Research Unit of Non-Coding RNAs and Genome Editing, Department of Internal Medicine, Division of Clinical Oncology, Medical University of Graz, 8036 Graz, Austria.

The emergence of SARS-CoV-2 in 2019 has caused a major health and economic crisis around the globe. Gaining knowledge about its attributes and interactions with human host cells is crucial. Non-coding RNAs (ncRNAs) are involved in the host cells' innate antiviral immune response. In RNA interference, microRNAs (miRNAs) may bind to complementary sequences of the viral RNA strand, forming an miRNA-induced silencing complex, which destroys the viral RNA, thereby inhibiting viral protein expression. There are several targets for human miRNAs on SARS-CoV-2's RNA, most of which are in the 5' and 3' untranslated regions. Mutations of the viral genome causing the creation or loss of miRNA binding sites may have crucial effects on SARS-CoV-2 pathogenicity. In addition to mediating immunity, the ncRNA landscape of host cells further influences their susceptibility to virus infection, as certain miRNAs are essential in the regulation of cellular receptors that are necessary for virus invasion. Conversely, virus infection also changes the host ncRNA expression patterns, possibly augmenting conditions for viral replication and dissemination. Hence, ncRNAs typically upregulated in SARS-CoV-2 infection could be useful biomarkers for disease progression and severity. Understanding these mechanisms could provide further insight into the pathogenesis and possible treatment options against COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v12121374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761185PMC
December 2020

Evaluation of Blood-based Biomarkers for Prediction of Response in Carboplatin-treated Metastatic Castration-resistant Prostate Cancer Patients.

In Vivo 2020 Nov-Dec;34(6):3631-3638

Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria

Background/aim: Carboplatin-containing treatment regimens demonstrate moderate efficacy in metastatic castration-resistant prostate cancer (mCRPC). In this study, we retrospectively analyzed the efficacy of carboplatin in relation to blood-based parameters.

Patients And Methods: A retrospective chart review was performed for 20 patients with mCRPC who received carboplatin in a single center.

Results: Median overall survival was 3.8 months (95%CI=1.5-7.1), median progression-free survival was 1.7 months. We observed two partial remissions (PR, 10%), four stable diseases (SD, 20%) and 14 disease progressions (PD, 70%), resulting in a clinical benefit rate of 30%. A doubling of NSE (neurone specific enolase) values was associated with a 19% absolute higher response rate (95%CI=14-23, p=0.027). All other laboratory parameters failed as predictive markers of response to carboplatin. In univariate Cox regression analysis, only NSE was significantly associated with impaired PFS (HR=0.7, 95%CI=0.56-0.96, p=0.030).

Conclusion: Carboplatin showed moderate efficacy against mCRPC in this unselected population of patients and NSE levels may help to predict the success of this treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.12209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811620PMC
August 2020

Stage-Specific Value of Carbohydrate Antigen 19-9 and Carcinoembryonic Antigen Serum Levels on Survival and Recurrence in Pancreatic Cancer: A Single Center Study and Meta-Analysis.

Cancers (Basel) 2020 Oct 14;12(10). Epub 2020 Oct 14.

Department of Surgery, Leiden University Medical Center, 2300RC Leiden, The Netherlands.

This study aimed to determine the stage-specific prognostic value of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) serum levels at diagnosis on overall survival (OS) and time to local recurrence or distant metastases in patients with pancreatic ductal adenocarcinoma (PDAC). Consecutive PDAC patients, discussed at multidisciplinary team meetings from 2013 through 2017, were reviewed. Prognostic factors were stage-specific (resection vs. advanced PDAC) evaluated in Cox proportional hazard models. Additionally, a systematic literature search and meta-analysis was performed, as current literature is lacking a complete overview of used cut-off values and the added value of CEA as prognostic marker. In the retrospective cohort, elevated CA19-9 (>305 kU/L) level was independently associated with poor OS (Hazard ratio (HR): 1.72(1.31-2.26)) and early recurrence (HR: 1.74(1.06-2.86)), whereas CEA was not significantly associated. The meta-analysis showed that both elevated CA19-9 and CEA serum levels were predictors for poor OS (pooled HR: 1.29(1.17-1.42) and HR: 1.51(1.33-1.73), respectively). In the resected cohort, elevated CA19-9 level was significantly associated with early recurrence (pooled HR: 2.41(1.77-3.29)), whereas CEA was not. Elevated CA19-9 serum level appear to be an independent prognostic factor for poor OS and early recurrence in PDAC patients, whereas the prognostic value of CEA is disputable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12102970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602123PMC
October 2020

Circulating Non-coding RNAs in Renal Cell Carcinoma-Pathogenesis and Potential Implications as Clinical Biomarkers.

Front Cell Dev Biol 2020 15;8:828. Epub 2020 Sep 15.

Research Unit of Non-Coding RNAs and Genome Editing, Division of Clinical Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.

Liquid biopsy-the determination of circulating cells, proteins, DNA or RNA from biofluids through a "less invasive" approach-has emerged as a novel approach in all cancer entities. Circulating non-(protein) coding RNAs including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and YRNAs can be passively released by tissue or cell damage or actively secreted as cell-free circulating RNAs, bound to lipoproteins or carried by exosomes. In renal cell carcinoma (RCC), a growing body of evidence suggests circulating non-coding RNAs (ncRNAs) such as miRNAs, lncRNAs, and YRNAs as promising and easily accessible blood-based biomarkers for the early diagnosis of RCC as well as for the prediction of prognosis and treatment response. In addition, circulating ncRNAs could also play a role in RCC pathogenesis and progression. This review gives an overview over the current study landscape of circulating ncRNAs and their involvement in RCC pathogenesis as well as their potential utility as future biomarkers in RCC diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.00828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523432PMC
September 2020

Involvement of Long Non-Coding RNAs (lncRNAs) in Tumor Angiogenesis.

Noncoding RNA 2020 Sep 25;6(4). Epub 2020 Sep 25.

Research Unit of Non-Coding RNAs and Genome Editing in Cancer, Division of Clinical Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria.

Long non-coding RNAs (lncRNAs) are defined as non-protein coding transcripts with a minimal length of 200 nucleotides. They are involved in various biological processes such as cell differentiation, apoptosis, as well as in pathophysiological processes. Numerous studies considered that frequently deregulated lncRNAs contribute to all hallmarks of cancer including metastasis, drug resistance, and angiogenesis. Angiogenesis, the formation of new blood vessels, is crucial for a tumor to receive sufficient amounts of nutrients and oxygen and therefore, to grow and exceed in its size over the diameter of 2 mm. In this review, the regulatory mechanisms of lncRNAs are described, which influence tumor angiogenesis by directly or indirectly regulating oncogenic pathways, interacting with other transcripts such as microRNAs (miRNAs) or modulating the tumor microenvironment. Further, angiogenic lncRNAs occurring in several cancer types such as liver, gastrointestinal cancer, or brain tumors are summarized. Growing evidence on the influence of lncRNAs on tumor angiogenesis verified these transcripts as potential predictive or diagnostic biomarkers or therapeutic targets of anti-angiogenesis treatment. However, there are many unsolved questions left which are pointed out in this review, hence driving comprehensive research in this area is necessary to enable an effective use of lncRNAs as either therapeutic molecules or diagnostic targets in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ncrna6040042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711482PMC
September 2020

C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study.

Cancers (Basel) 2020 Aug 17;12(8). Epub 2020 Aug 17.

Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.

Background: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents.

Methods: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort ( = 90), confirm these findings in an external validation cohort ( = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively.

Results: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16-1.63, < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18-1.71, < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51-0.92, = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15-1.30, < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14-154.54, = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83-0.99, = 0.036), respectively.

Conclusion: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12082319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464328PMC
August 2020

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System.

Cancers (Basel) 2020 Aug 3;12(8). Epub 2020 Aug 3.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Available systemic treatment options for cancers of the genitourinary system have experienced great progress in the last decade. However, a large proportion of patients eventually develop resistance to treatment, resulting in disease progression and shorter overall survival. Biomarkers indicating the increasing resistance to cancer therapies are yet to enter clinical routine. Long non-coding RNAs (lncRNA) are non-protein coding RNA transcripts longer than 200 nucleotides that exert multiple types of regulatory functions of all known cellular processes. Increasing evidence supports the role of lncRNAs in cancer development and progression. Additionally, their involvement in the development of drug resistance across various cancer entities, including genitourinary malignancies, are starting to be discovered. Consequently, lncRNAs have been suggested as factors in novel therapeutic strategies to overcome drug resistance in cancer. In this review, the existing evidences on lncRNAs and their involvement in mechanisms of drug resistance in cancers of the genitourinary system, including renal cell carcinoma, bladder cancer, prostate cancer, and testicular cancer, will be highlighted and discussed to facilitate and encourage further research in this field. We summarize a significant number of lncRNAs with proposed pathways in drug resistance and available reported studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12082148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463785PMC
August 2020

Hazard Curves for Tumor Recurrence and Tumor-Related Death Following Esophagectomy for Esophageal Cancer.

Cancers (Basel) 2020 Jul 27;12(8). Epub 2020 Jul 27.

Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria.

Background: The knowledge of both patterns and risk of relapse following resection for esophageal cancer is crucial for establishing appropriate surveillance schedules. The aim of this study was to evaluate the pattern of hazards for tumor recurrence and tumor-related death in the postoperative long-term follow-up after esophagectomy.

Methods: Retrospective single-center analysis of 362 patients, with resected esophageal cancer. Multivariate Cox proportional hazard model was used.

Results: A total of 192 (53%) had postoperative tumor recurrence. The relapse patterns of adenocarcinoma and squamous-cell carcinoma showed that each had a single peak, 12 months after surgery. After induction there was one peak at 5 months, the non-induced patients peaked 11 months, postoperatively. At 18 months, the recurrence hazard declined sharply in all cases. The hazard curves for tumor-related death were bimodal for adenocarcinoma, with two peaks at 6 and 22 months and one single peak for squamous-cell carcinoma at 18 months after surgery, showing pronounced decline later on.

Conclusion: In curatively resected esophageal cancer, both tumor recurrence hazard and hazard for tumor-related death showed distinct, partly bimodal patterns. It could be justified to intensify the surveillance during the first two postoperative years by initiating a close-meshed follow-up to detect and treat tumor recurrence, as early as possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12082066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466063PMC
July 2020

Diabetes mellitus is independently associated with adverse clinical outcome in soft tissue sarcoma patients.

Sci Rep 2020 07 24;10(1):12438. Epub 2020 Jul 24.

Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Diabetes mellitus (DM) and hyperglycemia are known predictors of adverse outcome in different tumor entities. The present study investigated the effect of DM and pre-surgery blood glucose levels on cancer specific survival (CSS), overall survival (OS), and disease-free survival (DFS) in non-metastatic soft tissue sarcoma (STS) patients. A total of 475 STS patients who underwent curative resection were included in this retrospective study. CSS, DFS, and OS were assessed using Kaplan-Meier curves. The association between pre-existing DM as well as mean pre-surgery blood glucose levels and all 3 survival endpoints was analyzed using Cox-hazard proportional (for OS and DFS) and competing risk regression models (for CSS). In unadjusted analysis, DM was significantly associated with adverse CSS (sub-hazard ratio [SHR]: 2.14, 95% confidence interval [CI] 1.18-3.90, p = 0.013) and OS (hazard ratio [HR]: 2.05, 95% CI 1.28-3.28) and remained significant after adjusting for established prognostic factors (CSS: adjusted SHR 2.33, 95% CI 1.21-4.49, p = 0.012; OS: adjusted HR 1.96, 95% CI 1.17-3.28, p = 0.010), respectively. There was no significant association of DM with DFS (p = 0.149). The mean pre-surgery glucose levels were not significantly associated with inferior outcome (CSS: p = 0.510, OS: p = 0.382 and DFS: p = 0.786). This study shows, that DM represents a negative prognostic factor for clinical outcome in STS patients after curative resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-69237-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382498PMC
July 2020

Estimation versus measurement of the glomerular filtration rate for kidney function assessment in patients with cancer undergoing cisplatin-based chemotherapy.

Sci Rep 2020 07 8;10(1):11219. Epub 2020 Jul 8.

Division of Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Glomerular filtration rate (GFR) assessment is indicated before every administration of cisplatin. The optimal modality for this purpose [GFR measurement by urinary Creatinine Clearance (uCrCl) versus GFR estimation (eGFR) by the CKD-EPI formula versus both] is unclear. We investigated whether eGFR only is safe in this setting. Paired uCrCl and eGFR determinations from 470 cisplatin cycles from 121 patients were analyzed [median age: 55 years; most frequent tumor site: genitourinary (45%); palliative treatment: n = 41 (34%)]. Primary endpoint was the proportion of cycles with uCrCl < 50 ml/min/1.73m and eGFR ≥ 50 ml/min/1.73m (i.e. a "false negative" result when only determining eGFR). The primary endpoint occurred in 8 of 470 cisplatin cycles (1.7%, 95%CI 0.5-2.9). In all 8 events, uCrCl was lower than eGFR (mean uCrCl vs. eGFR: 43 versus 112 ml/min/1.73m). The uCrCl was re-measured in all patients, and showed normal results in all but 1 patient. None of these events precluded the administration of cisplatin at the planned date, and no subsequent cases of acute nephrotoxicity occurred. Overall agreement between uCrCl and eGFR was low, with qualitative analysis suggesting frequent incompliance with 24-h urine collection. We conclude that an eGFR is sufficient for assessing kidney function in patients with cancer undergoing cisplatin therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-68010-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343883PMC
July 2020

Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer.

Noncoding RNA 2020 Jul 6;6(3). Epub 2020 Jul 6.

Research Unit of Non-Coding RNAs and Genome Editing in Cancer, Division of Clinical Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz; Medical University of Graz, 8036 Graz, Austria.

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ncrna6030027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549355PMC
July 2020

The Lipase/Amylase Ratio (LAR) in Peripheral Blood Might Represent a Novel Prognostic Marker in Patients with Surgically Resectable Pancreatic Cancer.

Cancers (Basel) 2020 Jul 5;12(7). Epub 2020 Jul 5.

Division of Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria.

Pancreatic enzymes might play a pivotal role in the pathophysiology and prognosis of pancreatic cancer. The aim of this study is to investigate the lipase/amylase ratio (LAR), representing a marker previously used in the differentiation of pancreatitis, as a potential prognostic marker in pancreatic cancer. Data from 157 surgically treated patients with ductal pancreatic adenocarcinoma and 351 patients with metastatic disease were evaluated retrospectively. Cancer-specific survival (CSS) was considered the endpoint of the study. After applying Kaplan-Meier curve analysis, uni- and multivariate Cox regression models were calculated to evaluate the prognostic relevance of LAR. An elevated LAR at diagnosis of localized pancreatic cancer was significantly associated with higher CA19-9 levels ( < 0.05). In univariate analysis, we observed an increased LAR as a significant factor for lower CSS in localized pancreatic cancer patients (HR = 1.63; 95% CI = 1.12-2.36; = 0.01), but not in metastatic patients (HR = 1.12; 95% CI = 0.87-1.43; = 0.363). In multivariate analysis, including age, gender, tumor stage, Karnofsky Performance Status, tumor grade, administration of chemotherapy and the LAR, an increased LAR was confirmed to represent an independent prognostic factor regarding CSS (HR = 1.81; 95% CI = 1.17-2.77; = 0.007) in localized pancreatic cancer patients. In conclusion, our study identified the LAR as an independent prognostic factor in surgically treated pancreatic cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12071798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408133PMC
July 2020

The Role of Immunohistochemical Overexpression of p53 as Adverse Prognostic Factor in Primary Testicular Diffuse Large B Cell Lymphoma.

Pathol Oncol Res 2020 Oct 29;26(4):2831-2833. Epub 2020 Jun 29.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 38D, A-8036, Graz, Austria.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12253-020-00864-6DOI Listing
October 2020

External validation of the prognostic relevance of the advanced lung cancer inflammation index (ALI) in pancreatic cancer patients.

Cancer Med 2020 08 14;9(15):5473-5479. Epub 2020 Jun 14.

Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.

Background: The advanced lung cancer inflammation index (ALI) was first introduced for prognosis prediction in lung cancer patients and since then evaluated in several other malignancies. However, in pancreatic cancer (PC) the ALI and its prognostic utility were only investigated in a comparably small and specific cohort of locally advanced PC patients treated with chemoradiotherapy.

Methods: In our single-center cohort study, we included 429 patients with histologically verified PC who were treated between 2003 and 2015 at our academic institution. The ALI was defined as body mass index (BMI; kg/m ) × serum albumin levels (g/dL)/neutrophil-lymphocyte ratio (NLR) and we defined the optimal cutoff for biomarker dichotomization by ROC-analysis. Kaplan-Meier method as well as uni- and multivariate Cox regression Hazard proportional models were implemented to assess the prognostic potential of ALI in PC patients. We considered cancer-specific survival (CSS) as the primary endpoint of the study.

Results: The ALI showed a significant negative correlation with CA19-9 levels and C-reactive protein levels whereas we found an association with localized tumor stage and better performance status (P < .05 for all mentioned variables). As opposed to patients with a high ALI, decreased ALI was significantly associated with shorter CSS (HR = 0.606, 95% CI: 0.471-0.779, P = .001). Multivariate analysis demonstrated tumor grade, tumor stage, chemotherapy, C-reactive protein levels, and CA19-9 levels to independently predict for CSS (all P < .05). In contrast the ALI failed to independently predict for CSS in the performed multivariate models (HR = 0.878, 95% CI: 0.643-1.198, P = .411).

Conclusion: In this large cohort of PC patients, the ALI did not complement existing clinicopathological factors for outcome determination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402815PMC
August 2020

Long Non-Coding RNA PANTR1 is Associated with Poor Prognosis and Influences Angiogenesis and Apoptosis in Clear-Cell Renal Cell Cancer.

Cancers (Basel) 2020 May 10;12(5). Epub 2020 May 10.

Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

POU3F3 adjacent non-coding transcript 1 (PANTR1) is an oncogenic long non-coding RNA with significant influence on numerous cellular features in different types of cancer. No characterization of its role in renal cell carcinoma (RCC) is yet available. In this study, PANTR1 expression was confined to human brain and kidney tissue and was found significantly up-regulated in clear-cell renal cell carcinoma tissue (ccRCC) compared to non-cancerous kidney tissue in two independent cohorts ( < 0.001 for both cohorts). In uni- and multivariate Cox regression analysis, ccRCC patients with higher levels of PANTR1 showed significantly poorer disease-free survival in our own respective cohort ( = 175, hazard ratio: 4.3, 95% confidence interval: 1.45-12.75, = 0.008) in accordance with significantly poorer overall survival in a large The Cancer Genome Atlas database (TCGA) cohort ( = 530, hazard ratio: 2.19, 95% confidence interval: 1.59-3.03, ≤ 0.001). To study the underlying cellular mechanisms mediated by varying levels of PANTR1 in kidney cancer cells, we applied siRNA-mediated knock-down experiments in three independent ccRCC cell lines (RCC-FG, RCC-MF, 769-P). A decrease in PANTR1 levels led to significantly reduced cellular growth through activation of apoptosis in all tested cell lines. Moreover, as angiogenesis is a critical driver in ccRCC pathogenesis, we identified that PANTR1 expression is critical for in vitro tube formation and endothelial cell migration ( < 0.05). On the molecular level, knock-down of PANTR1 led to a decrease in Vascular Endothelial growth factor A (VEGF-A) and cell adhesion molecule laminin subunit gamma-2 (LAMC2) expression, corroborated by a positive correlation in RCC tissue (for VEGF-A = 0.19, < 0.0001, for LAMC2 = 0.13, = 0.0028). In conclusion, this study provides first evidence that PANTR1 has a relevant role in human RCC by influencing apoptosis and angiogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12051200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281347PMC
May 2020

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Cancers (Basel) 2020 May 4;12(5). Epub 2020 May 4.

Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8010 Graz, Austria.

The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan-Meier curve, and both univariate and multivariate Cox proportional models. BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively ( < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129-1.754, = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10-1.82; = 0.006) were identified as independent prognostic factors. : Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12051154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281496PMC
May 2020

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer.

Int J Mol Sci 2020 Apr 23;21(8). Epub 2020 Apr 23.

Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), 8036 Graz, Austria.

The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21082969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215867PMC
April 2020

Long Non-Coding RNAs in Biliary Tract Cancer-An Up-to-Date Review.

J Clin Med 2020 Apr 22;9(4). Epub 2020 Apr 22.

Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.

The term long non-coding RNA (lncRNA) describes non protein-coding transcripts with a length greater than 200 base pairs. The ongoing discovery, characterization and functional categorization of lncRNAs has led to a better understanding of the involvement of lncRNAs in diverse biological and pathological processes including cancer. Aberrant expression of specific lncRNA species was demonstrated in various cancer types and associated with unfavorable clinical characteristics. Recent studies suggest that lncRNAs are also involved in the development and progression of biliary tract cancer, a rare disease with high mortality and limited therapeutic options. In this review, we summarize current findings regarding the manifold roles of lncRNAs in biliary tract cancer and give an overview of the clinical and molecular consequences of aberrant lncRNA expression as well as of underlying regulatory functions of selected lncRNA species in the context of biliary tract cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9041200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231154PMC
April 2020

Generation of An Endogenous FGFR2-BICC1 Gene Fusion/58 Megabase Inversion Using Single-Plasmid CRISPR/Cas9 Editing in Biliary Cells.

Int J Mol Sci 2020 Apr 2;21(7). Epub 2020 Apr 2.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Fibroblast growth factor receptor 2 () gene fusions are oncogenic drivers in 10-15% of intrahepatic cholangiocarcinoma (CCA), yet currently there are no cell lines publically available to study endogenous gene fusions. The ability of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to generate large yet precise chromosomal rearrangements has presented the possibility of engineering endogenous gene fusions for downstream studies. In this technical report, we describe the generation of an endogenous -Bicaudal family RNA binding protein 1 () fusion in multiple independent cholangiocarcinoma and immortalized liver cell lines using CRISPR. is the most common fusion partner in CCA, and the fusion arises as a consequence of a 58-megabase-sized inversion on chromosome 10. We replicated this inversion to generate a fusion product that is identical to that seen in many human CCA. Our results demonstrate the feasibility of generating large megabase-scale inversions that faithfully reproduce human cancer aberrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21072460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178239PMC
April 2020