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Targeted RNA N6-Methyladenosine Demethylation inhibits cell migration in colorectal cancer cells [MeRIP-seq]

ABSTRACT: Colorectal cancer liver metastasis (CRLM) remains a significant challenge in the treatment of colorectal cancer (CRC). N6-methyladenosine (m6A) as a new layer of epigenetic RNA modification is closely linked to various mechanisms of tumor metastasis, offering new avenues for targeted therapies. However, the role of m6A-mediated mechanisms underlying colorectal liver metastasis is still unclear. In this study, we identified a novel m6A-modified transcriptional factor BTB/POZ domain protein ZBTB7A (zinc finger and BTB domain-containing 7A) using integrative m6A-sequencing (MeRIP-seq), RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq) analyses, and investigated the functional signiﬁcance and underlying mechanisms of ZBTB7A as a promoting factor in liver metastasis of CRC. Mechanically, ZBTB7A could be positively regulated by m6A methyltransferase METTL3 and promote the process of CRLM through ARHGAP26-mediated Rho GTPases signaling pathway in a m6A-dependent manner. More importantly, we also applied a targeted RNA m6A erasure (TRME) system to focus methylation on a specific site within a transcript of interest rather altering global levels of m6A abundance and demonstrated that temporal m6A erasure on a single site of ZBTB7A is suﬃcient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m6A-mediated CRLM and positions m6A precise editing as a promising therapy in the preclinical treatment of tumor metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319983 | GEO | 2026/09/02

REPOSITORIES: GEO

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Targeted RNA N6-Methyladenosine Demethylation inhibits cell migration in colorectal cancer cells [RNA-seq]

Project description:Colorectal cancer liver metastasis (CRLM) remains a significant challenge in the treatment of colorectal cancer (CRC). N6-methyladenosine (m6A) as a new layer of epigenetic RNA modification is closely linked to various mechanisms of tumor metastasis, offering new avenues for targeted therapies. However, the role of m6A-mediated mechanisms underlying colorectal liver metastasis is still unclear. In this study, we identified a novel m6A-modified transcriptional factor BTB/POZ domain protein ZBTB7A (zinc finger and BTB domain-containing 7A) using integrative m6A-sequencing (MeRIP-seq), RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq) analyses, and investigated the functional signiﬁcance and underlying mechanisms of ZBTB7A as a promoting factor in liver metastasis of CRC. Mechanically, ZBTB7A could be positively regulated by m6A methyltransferase METTL3 and promote the process of CRLM through ARHGAP26-mediated Rho GTPases signaling pathway in a m6A-dependent manner. More importantly, we also applied a targeted RNA m6A erasure (TRME) system to focus methylation on a specific site within a transcript of interest rather altering global levels of m6A abundance and demonstrated that temporal m6A erasure on a single site of ZBTB7A is suﬃcient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m6A-mediated CRLM and positions m6A precise editing as a promising therapy in the preclinical treatment of tumor metastasis.

2026-09-02 | GSE302405 | GEO

Differential regulation of extracellular matrix proteins in three recurrent liver metastases of a single patient with colorectal cancer

Project description:Colorectal cancer (CRC) patients suffer from the second highest mortality among all cancer entities. In half of all CRC patients, colorectal cancer liver metastases (CRLM) can be observed. Metastatic colorectal cancer is associated with poor overall survival and limited treatment options. Even after successful surgical resection of the primary tumor, metachronous liver metastases occur in one out of eight cases. The only available curative intended treatment is hepatic resection, but metachronous CRLM frequently recur after approximately one year. In this study, we performed a proteome analysis of three recurrent liver metastases of a single CRC patient by mass spectrometry. Despite surgical resection of the primary CRC and adjuvant chemotherapy plus cetuximab treatment, the patient developed three metachronous CRLM which occurred consecutively after 9, 21 and 31 months. We identified a set of 1,132 proteins expressed in the three metachronous CRLM, of which 481 were differentially regulated, including 81 proteins that were associated with the extracellular matrix (ECM). 56 ECM associated proteins were identified as upregulated in the third metastasis, 26 (46%) of which were previously described as negative prognostic markers in CRC, including tenascin C, nidogen 1, fibulin1 and vinculin. These data may reflect an ascending trend of malignancy from the first to the third metachronous colorectal cancer liver metastasis. Additionally, the results indicate different ECM phenotypes for recurrent metachronous metastasis, associated with different grades of malignancy and highlights the importance of individual analysis of molecular features in different, consecutive metastatic events in a single patient.

2021-09-09 | PXD020109 | Pride

Down-regulation of collagen hydroxylation in colorectal liver metastasis

Project description:Collagen, a major component of the extracellular matrix, is significantly upregulated in colorectal liver metastasis (CRLM) compared to liver tissue. Expression levels of specific collagen types in CRLM resemble those in colorectal cancer (CRC) and colon tissue. We investigated whether the collagen hydroxylation pattern from the primary tumor also migrates with the metastatic tumor. The degree of collagen alpha-1(I) hydroxylation in colon, CRC, liver, and CRLM tissue in the same individuals (n=14) was studied with mass spectrometry. The degree of hydroxylation was investigated in 36 collagen alpha-1(I) peptides, which covered 54% of the triple helical region. The average degree of hydroxylation in liver tissue was similar to that in colon tissue. The overall degree of hydroxylation was significantly lower (9% +/- 14%) in CRC tissue and also significantly lower (12% +/-22%) in CRLM tissue compared to colon or liver tissue. Still, in previous research of liver and CRLM enzymes involved in collagen hydroxylation were found to be upregulated, whereas P4HB (4-prolyl hydroxylase beta unit) was downregulated. Furthermore, 11 peptides are present with a specific number of hydroxylations that are significantly different between CRLM and liver tissue; these peptides could be candidates for the detection of CRLM. For one of these eleven peptides, a matching naturally occurring peptide in urine has been identified as being significantly different between patients suffering from CRLM and healthy controls. We conclude that the degree of hydroxylation in CRC and CRLM tumor tissue is in general significantly downregulated in comparison to healthy colon and liver tissue. The hydroxylation pattern in CRLM resemble partly the pattern in liver, primary colorectal cancer and colon.

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Tissue-specific immunosuppressive and proliferating macrophages fuel early metastatic progression of human colorectal cancer to liver

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2025-08-11 | GSE298084 | GEO

FGF19 induces the inflammatory phenotype of LX-2 cells

Project description:Liver metastasis is the main cause of death for human colorectal cancer (CRC), thus effective biomarkers and therapeutic target of colorectal cancer liver metastasis (CRLM) are urgently needed. Here, we report that FGF19 mediated the polarization of hepatic stellate cells to inflammatory CAFs by activating the autocrine effect of IL-1α via JAK2-STAT3 pathway. FGF19-induced iCAFs produced complement C5a and IL-1β to enhance neutrophil extracellular traps (NETs) formation in liver metastases, which in turn accelerated the liver colonization of CRC cells.

2023-07-03 | GSE215882 | GEO

Distribution of Collagen in Colorectal Liver Metastasis and Normal Liver tissue

Project description:We determined whether collagen is upregulated in colorectal liver metastasis tissue (CRLM). We previously showed that naturally occurring peptides of collagen type I were elevated in the urine of patients with colorectal liver metastasis (CRLM). CRLM tissue was compared to healthy adjacent liver tissue (controls) using high resolution mass spectrometry. Twenty-two different collagen alpha chains were identified, 19 of which were significantly upregulated (P<0.05) in CRLM tissue compared with control tissue. We observed expression of four collagen alpha chains which were absent or low expressed in healthy colon and control tissue, but were highly present in CRC and CRLM tissues analyzed. This expression pattern was also observed for six non-collagen colon specific proteins. Two of these proteins (CDH17 and PPP1R1B/DARP-32) were not known to be differently expressed in CRLM in comparison to healthy liver tissue. Furthermore, 16 of 20 identified proteins related to collagen synthesis were upregulated, indicating increased synthesis of collagen in CRLM. Cross-validation of the mass spectrometry data with immunohistochemistry for collagen type XII confirmed the significant upregulation of collagen type XII in CRLM. This study shows that the majority of collagen types are upregulated in CRLM compared to control tissue most likely as a result of an increased collagen turnover and changes in the collagen supramolecular structure. This research provides further understanding of morphologic changes in extracellular matrix of CRLM and the finding of proteins and peptides that might be specific for tumor metastasis in liquid biopsies.

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Th17 cells secrete TWEAK to trigger epithelial-mesenchymal transition and promote colorectal cancer liver metastasis (RNA-seq)

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Th17 cells secrete TWEAK to trigger epithelial-mesenchymal transition and promote colorectal cancer liver metastasis (scRNA-seq)

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