bims-instec 2023-12-31 papers

Epigenetics. 2024 Dec;19(1): 2298058

N6-methyladenosine methylation analysis of long noncoding RNAs and mRNAs in 5-FU-resistant colon cancer cells.

Jie Lai, Zhiyong Zhou, Kan Hu, HongLong Yu, Xingyao Su, Xiaoqiang Niu, Huizi Li, Shengxun Mao.

N6 methyladenosine (m6A), methylation at the sixth N atom of adenosine, is the most common and abundant modification in mammalian mRNAs and non-coding RNAs. Increasing evidence shows that the alteration of m6A modification level could regulate tumour proliferation, metastasis, self-renewal, and immune infiltration by regulating the related expression of tumour genes. However, the role of m6A modification in colorectal cancer (CRC) drug resistance is unclear. Here, MeRIP-seq and RNA-seq techniques were utilized to obtain mRNA, lncRNA expression, and their methylation profiles in 5-Fluorouracil (5-FU)-resistant colon cancer HCT-15 cells and control cells. In addition, we performed detailed bioinformatics analysis as well as in vitro experiments of lncRNA to explore the function of lncRNA with differential m6A in CRC progression and drug resistance. In this study, we obtained the m6A methylomic landscape of CRC cells and resistance group cells by MeRIP-seq and RNA-seq. We identified 3698 differential m6A peaks, of which 2224 were hypermethylated, and 1474 were hypomethylated. Among the lncRNAs, 60 were hypermethylated, and 38 were hypomethylated. GO and KEGG analysis annotations showed significant enrichment of endocytosis and MAPK signalling pathways. Moreover, knockdown of lncRNA ADIRF-AS1 and AL139035.1 promoted CRC proliferation and invasive metastasis in vitro. lncRNA- mRNA network showed that ADIRF-AS1 and AL139035.1 May play a key role in regulating drug resistance formation. We provide the first m6A methylation profile in 5-FU resistance CRC cells and analyse the functions of differential m6A-modified mRNAs and lncRNAs. Our results indicated that differential m6A RNAs were significantly associated with MAPK signalling and endocytosis after induction of 5-FU resistance. Knockdown of LncRNA ADIRF-AS1 and AL139035.1 promotes CRC progression and might be critical in regulating drug resistance formation.

Keywords: M6A methylation; MeRIP-seq; colorectal cancer; drug-resistance

DOI: https://doi.org/10.1080/15592294.2023.2298058

Med Oncol. 2023 Dec 27. 41(1): 34

Intestinal epithelial SNAI1 promotes the occurrence of colorectal cancer by enhancing EMT and Wnt/β-catenin signaling.

Furong Qing, Junxia Xue, Lina Sui, Qiuxiang Xiao, Tao Xie, Yayun Chen, Junyun Huang, Zhiping Liu.

Colorectal cancer (CRC) is a prevalent cause of cancer and mortality on a global scale. SNAI1, a member of the zinc finger transcription superfamily, is a significant contributor to embryonic development and carcinogenesis through the process of epithelial-mesenchymal transition (EMT). While prior research utilizing CRC cells and clinical data has demonstrated that SNAI1 facilitates CRC progression through diverse mechanisms, the precise manner in which epithelial SNAI1 regulates CRC development in vivo remains unclear. In this study, colitis and colitis-associated CRC were induced through the use of intestinal epithelium-specific Snai1 knockout (Snai1 cKO) mice. Our findings indicate that Snai1 cKO mice exhibit a reduced susceptibility to acute colitis and colitis-associated CRC compared to control mice. Western-blot analysis of colon tissues revealed that Snai1 cKO mice exhibited a higher overall apoptosis level during tumor formation than control mice. No significant differences were observed in the activation of the classical p53 signaling pathway. However, Snai1 cKO mice exhibited weakened EMT and Wnt/β-catenin pathway activation. In summary, our study has provided evidence in vivo that the intestinal epithelial SNAI1 protein suppresses apoptosis, amplifies the EMT, and activates the Wnt/β-catenin signaling pathways in both early and late phases of CRC formation, thus promoting the development and progression of colitis-associated CRC.

Keywords: Apoptosis; Colitis; Colorectal cancer; EMT; SNAI1; Wnt/β-catenin

DOI: https://doi.org/10.1007/s12032-023-02253-w

Cell Rep. 2023 Dec 26. pii: S2211-1247(23)01628-5. [Epub ahead of print]43(1): 113616

Developmental role of macrophages modeled in human pluripotent stem cell-derived intestinal tissue.

Andrew T Song, Renata H M Sindeaux, Yuanyi Li, Hicham Affia, Tapan Agnihotri, Severine Leclerc, Patrick Piet van Vliet, Mathieu Colas, Jean-Victor Guimond, Natalie Patey, Lara Feulner, Jean-Sebastien Joyal, Elie Haddad, Luis Barreiro, Gregor Andelfinger.

Macrophages populate the embryo early in gestation, but their role in development is not well defined. In particular, specification and function of macrophages in intestinal development remain little explored. To study this event in the human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrate into the organoid, proliferate, and occupy the emerging microanatomical niches of epithelial crypts and ganglia. They also acquire a transcriptomic profile similar to that of fetal intestinal macrophages and display tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to the regulation of metabolism and growth of the developing intestine.

Keywords: CP: Stem cell research; CSF1; OSM; enteric neuron; glycolysis; intestinal development; intestinal organoid; intestine; macrophage; metabolism; organ growth; pluripotent stem cell

DOI: https://doi.org/10.1016/j.celrep.2023.113616

J Clin Invest. 2023 Dec 28. pii: e169576. [Epub ahead of print]

Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage IV colorectal cancer.

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in UICC (Union for International Cancer Control) stage IV CRC patients. Insights into differential site-specific reconstitution of tumour cells and the corresponding tumour microenvironment are still missing. Here, we analysed the transcriptome of single cells derived from murine multivisceral CRC and delineated the inter-metastatic cellular heterogeneity regarding tumour epithelium, stroma and immune cells. Interestingly, we found an intercellular site-specific network of cancer associated fibroblasts and tumour epithelium during peritoneal metastasis as well as an autologous feed-forward loop in cancer stem cells. We furthermore deciphered a metastatic dysfunctional adaptive immunity by a loss of B cell dependent antigen presentation and consecutive effector T cell exhaustion. Furthermore, we demonstrated major similarities of this murine metastatic CRC model with human disease and -based on the results of our analysis- provided an auspicious site-specific immune modulatory treatment approach for stage IV CRC by intraperitoneal checkpoint inhibition.

Keywords: Cancer immunotherapy; Cell Biology; Colorectal cancer; Mouse models; Oncology

DOI: https://doi.org/10.1172/JCI169576