Biology subjects

Matej, R.

Publications and source records attributed to Matej, R..

3 recordsLinked to original sources

bioRxiv2024

TACSTD2 expression marks the early transition to colon adenomas

This study aimed to address new molecular events occurring in precancerous stages of colorectal cancer (CRC) by integrated analysis of gene expression data and DNA methylation profiles. Whole-transcriptome sequencing analysis was performed on 16 fresh frozen colorectal adenoma and matched mucosa specimens along with validation of candidates in an independent cohort of 20 fresh frozen paired adenoma and adjacent mucosa tissues as well as eight independent public datasets (335 cases). Genome-wide methylation profiles were determined for 5 adenoma pairs and confirmed by pyrosequencing on 20 tissue pairs used for validation. Functional analysis was performed in vitro and in vivo using the inflammation-associated azoxymethane/dextran sodium sulfate (AOM/DSS) and the sporadic colorectal carcinogenesis (six AOM injections) mouse models as well as ApcMin/+ mice. Candidates were investigated by immunohistochemical staining of human adenomas and early-stage (pT1) CRC tumors. A total of 1,917 differentially expressed genes and 148,191 differentially methylated CpG sites were detected in adenomas compared with adjacent mucosa samples. Based on the transcriptome data and relevance to CRC, TACSTD2, MMP7, MMP1, CLDN2, CLDN1, and ETV4, were selected for further validation. TACSTD2 promoter hypomethylation in adenoma tissues was validated in 20 additional tissue pairs and corresponded with increased TACSTD2 expression. TACSTD2 was also overexpressed in an in vitro transformation model of human colonic epithelial cells. The TACSTD2 protein TROP2 was elevated in human adenomas, pT1 tumors, and in murine adenomas, while it was absent in the unaffected adjacent mucosa. TROP2 overexpression might trigger the development of precancerous lesions and could help identify early transformation foci in colon biopsies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/620817v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1f23753org.highwire.dtl.DTLVardef@10e6abeorg.highwire.dtl.DTLVardef@181f500org.highwire.dtl.DTLVardef@fc0d38_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

TROP2 represents a negative prognostic factor in colorectal adenocarcinoma and its expression is associated with features of epithelial-mesenchymal transition and invasiveness

Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions and its expression is maintained in most colorectal cancer (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with transcription of genes involved in epithelial-mesenchymal transition, regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by {beta}-catenin and additionally by Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/{beta}-catenin signaling, YAP, and TROP2 expression. Simple SummaryColorectal cancer (CRC) is one of the most common cancers worldwide. While systemic treatment of CRC is based on chemotherapy, subsequent therapeutic options are far less effective. Trophoblast cell surface antigen 2 (TROP2) is highly expressed in many carcinomas, including CRC, where its expression correlates with poor prognosis. Anti-TROP2-targeted therapy was approved for the treatment of breast and urothelial carcinomas. We aimed to determine whether TROP2 is a suitable target for the treatment of CRC. We demonstrated that TROP2 expression in CRC correlates with lymph node metastasis and poor tumor differentiation. Analysis of mouse tumor models, patient-derived organoids, and tumor cells revealed that TROP2 expression is associated with features related to epithelial-mesenchymal transition and invasiveness. Our results suggest that TROP2 targeting may be a promising approach, especially in the early phase of treatment.

cancer biology↗

bioRxiv2021

Increased Occurrence of Treponema spp. and Double-species Infections in Patients with Alzheimer's Disease

ObjectiveAlthough the link between microbial infections and Alzheimers disease (AD) has been demonstrated in multiple studies, the involvement of pathogens in the development of AD remains unclear. Therefore, this theory beckons further systematic investigation. In this study, we have examined the association between the 10 most widely discussed viral and bacterial pathogens found in serum and cerebrospinal fluid (CSF) from patients with AD. MethodsWe have used an in-house developed multiplex PCR kit for simultaneous detection of five bacterial and five viral pathogens in serum and CSF from 50 AD patients and 53 healthy controls. Data analysis was performed with multiple statistical methods: Fishers exact test, chisquare goodness of fit test, and one-sample proportion test. ResultsWe observed an increased frequency of AD patients tested positive for Treponema spp. (AD: 62.2%; CTRL: 30.3%; p-value = 0.007). Furthermore, we confirmed a significantly higher prevalence of cases with two and more simultaneous infections in AD patients compared to controls (AD: 24%; CTRL 7.5%; p-value = 0.029). The studied pathogens were widespread equally in serum and CSF. Borrelia burgdorferi, human herpesvirus 7, and human cytomegalovirus were not detected in any of the studied samples. DiscussionAn increased prevalence of Treponema spp. and double-species infections in AD patients compared to the healthy controls provides further evidence of the association between microbial infections and AD. Paralleled analysis of multiple sample specimens provides complementary information and is advisable for future studies.

microbiology↗