SPARCL1 exhibits different expressions in left- and right-sided colon cancer and is downregulated via DNA methylation

Epigenomics ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 1269-1282
Author(s):  
Hanguang Hu ◽  
Dehao Wu ◽  
Xibo Liu ◽  
Haifeng Yu ◽  
Junxi Xu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Colon Cancer ◽  
Cancer Metastasis ◽  
Epigenetic Mechanism ◽  
Tissue Array ◽  
Cellular Motility ◽  
Colorectal Cancer Metastasis ◽  
Left And Right

Aim: The authors previously found that SPARCL1 functions to suppress colorectal cancer metastasis. Here, the epigenetic mechanism of SPARCL1 regulation and its relationship with clinicopathological features in colon cancer were investigated. Materials & methods: SPARCL1 expression was evaluated by immunohistochemistry staining in a tissue array containing 271 left-sided colon cancer samples and 257 right-sided colon cancer samples. In vivo and in vitro DNA methylation states were measured by biochemical sulfide potential assay. The transcription and DNA methylation states in cells were altered by siRNA or decitabine treatment, respectively. Cellular motility properties were compared through transwell assay. Results & conclusion: SPARCL1, mediated by its DNA methylation, may arrest colorectal carcinoma motility. Furthermore, SPARCL1 expression is higher and may have a specific prognostic value in left-sided colon cancer.

scholarly journals Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazim Husain ◽  
Domenico Coppola ◽  
Chung S. Yang ◽  
Mokenge P. Malafa
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Metastasis ◽  
Annexin V ◽  
Cancer Cell Growth ◽  
Ki 67 ◽  
Sox2 Expression ◽  
Tumour Metastasis

AbstractThe activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/β-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and β-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

scholarly journals Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Shiue-Wei Lai ◽  
Ming-Yao Chen ◽  
Oluwaseun Adebayo Bamodu ◽  
Ming-Shou Hsieh ◽  
Ting-Yi Huang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Cell Lines ◽  
Distant Metastasis ◽  
Cancer Metastasis ◽  
Lovo Cell ◽  
Promoting Effect ◽  
Colon Cancer Metastasis

Background. Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. Methods. Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). Results. The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. Conclusion. Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.

RNA interference of osteopontin inhibits in vitro and in vivo colon cancer metastasis

2004 ◽  
Vol 121 (2) ◽  
pp. 300
Author(s):  
P.Y. Wai ◽  
Z. Mi ◽  
H. Guo ◽  
S. Sarraf-Yazdi ◽  
B. Clary ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Rna Interference ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis

Role of endothelin a receptor in colon cancer metastasis: In vitro and in vivo evidence

2013 ◽  
Vol 53 (S1) ◽  
pp. E85-E91 ◽  
Author(s):  
Shaolin Nie ◽  
Jumei Zhou ◽  
Fei Bai ◽  
Bonian Jiang ◽  
Juying Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis ◽  
Endothelin A Receptor ◽  
Endothelin A

scholarly journals Hypoxia-Induced LIN28A mRNA Promotes the Metastasis of Colon Cancer in a Protein-Coding-Independent Manner

2021 ◽  
Vol 9 ◽  
Author(s):  
Mingjiao Weng ◽  
Yukuan Feng ◽  
Yan He ◽  
Weiwei Yang ◽  
Jing Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Mrna Level ◽  
Unexpected Finding ◽  
Independent Manner ◽  
Protein Coding ◽  
P Bodies

The hypoxic microenvironment is beneficial to the metastasis but not to the proliferation of cancer cells. However, the mechanisms regarding to hypoxia differentially regulating cancer metastasis and proliferation are largely unknown. In this study, we revealed that hypoxia induced the expression of LIN28A at mRNA level but segregated LIN28A mRNAs in the P-bodies and thus inhibits the production of LIN28A protein. This unexpected finding suggests that there may be non-coding role for LIN28A mRNA in the progression of colon cancer. We further showed that the non-coding LIN28A mRNA promotes the metastasis but not proliferation of colon cancer cells in vitro and in vivo. Mechanistically, we revealed that methionyl aminopeptidase 2 (METAP2) is one of the up-regulated metastasis regulators upon over-expression of non-coding LIN28A identified by mass spectrum, and confirmed that it is non-coding LIN28A mRNA instead of LIN28A protein promotes the expression of METAP2. Moreover, we demonstrated that knockdown of DICER abolished the promotional effects of non-coding LIN28A on the metastasis and METAP2 expression. Conclusively, we showed that hypoxia induces the production of LIN28A mRNAs but segregated them into the P-bodies together with miRNAs targeting both LIN28A and METAP2, and then promotes the metastasis by positively regulating the expression of METAP2. This study uncovered a distinctive role of hypoxia in manipulating the metastasis and proliferation by differently regulating the expression of LIN28A at mRNA and protein level.

scholarly journals PLAGL2 promotes epithelial–mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1

2019 ◽  
Vol 122 (4) ◽  
pp. 578-589
Author(s):  
Liang Wu ◽  
Zili Zhou ◽  
Shengbo Han ◽  
Jinhuang Chen ◽  
Zhengyi Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumours ◽  
Mesenchymal Transition ◽  
Exact Function ◽  
Colorectal Cancer Metastasis

Abstract Background We previously demonstrated that the pleomorphic adenoma gene like-2 (PLAGL2) is involved in the pathogenesis of Hirschsprung disease. Enhanced PLAGL2 expression was observed in several malignant tumours. However, the exact function of PLAGL2 and its underlying mechanism in colorectal cancer (CRC) remain largely unknown. Methods Immunohistochemical analysis of PLAGL2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of PLAGL2 in the progression of CRC. Results Enhanced PLAGL2 expression was significantly associated with EMT-related proteins in CRC. The data revealed that PLAGL2 promotes CRC cell proliferation, migration, invasion and EMT both in vitro and in vivo. Mechanistically, PLAGL2 promoted the expression of ZEB1. PLAGL2 enhanced the expression and nuclear translocation of β-catenin by decreasing its phosphorylation. The depletion of β-catenin neutralised the regulation of ZEB1 that was caused by enhanced PLAGL2 expression. The small-molecule inhibitor PNU-74654, also impaired the enhancement of ZEB1 that resulted from the modified PLAGL2 expression. The depletion of ZEB1 could block the biological function of PLAGL2 in CRC cells. Conclusions Collectively, our findings suggest that PLAGL2 mediates EMT to promote colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1.

scholarly journals Differential regulation of DNA methylation versus histone acetylation in cardiomyocytes during HHcy in vitro and in vivo: an epigenetic mechanism

2014 ◽  
Vol 46 (7) ◽  
pp. 245-255 ◽  
Author(s):  
Pankaj Chaturvedi ◽  
Anuradha Kalani ◽  
Srikanth Givvimani ◽  
Pradip Kumar Kamat ◽  
Anastasia Familtseva ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone Acetylation ◽  
Dna Methyltransferase ◽  
Epigenetic Mechanism ◽  
Dependent Manner ◽  
Histone Deacetylase 1 ◽  
H3k9 Acetylation ◽  
Dose Dependent

The mechanisms of homocysteine-mediated cardiac threats are poorly understood. Homocysteine, being the precursor to S-adenosyl methionine (a methyl donor) through methionine, is indirectly involved in methylation phenomena for DNA, RNA, and protein. We reported previously that cardiac-specific deletion of N-methyl-d-aspartate receptor-1 (NMDAR1) ameliorates homocysteine-posed cardiac threats, and in this study, we aim to explore the role of NMDAR1 in epigenetic mechanisms of heart failure, using cardiomyocytes during hyperhomocysteinemia (HHcy). High homocysteine levels activate NMDAR1, which consequently leads to abnormal DNA methylation vs. histone acetylation through modulation of DNA methyltransferase 1 (DNMT1), HDAC1, miRNAs, and MMP9 in cardiomyocytes. HL-1 cardiomyocytes cultured in Claycomb media were treated with 100 μM homocysteine in a dose-dependent manner. NMDAR1 antagonist (MK801) was added in the absence and presence of homocysteine at 10 μM in a dose-dependent manner. The expression of DNMT1, histone deacetylase 1 (HDAC1), NMDAR1, microRNA (miR)-133a, and miR-499 was assessed by real-time PCR as well as Western blotting. Methylation and acetylation levels were determined by checking 5′-methylcytosine DNA methylation and chromatin immunoprecipitation. Hyperhomocysteinemic mouse models (CBS+/−) were used to confirm the results in vivo. In HHcy, the expression of NMDAR1, DNMT1, and matrix metalloproteinase 9 increased with increase in H3K9 acetylation, while HDAC1, miR-133a, and miR-499 decreased in cardiomyocytes. Similar results were obtained in heart tissue of CBS+/− mouse. High homocysteine levels instigate cardiovascular remodeling through NMDAR1, miR-133a, miR-499, and DNMT1. A decrease in HDAC1 and an increase in H3K9 acetylation and DNA methylation are suggestive of chromatin remodeling in HHcy.

scholarly journals Quantitative Proteomics Analysis of Berberine-Treated Colon Cancer Cells Reveals Potential Therapy Targets

Biology ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 250
Author(s):  
Pengfei Li ◽  
Zhifang Hao ◽  
Huanhuan Liu ◽  
Bojing Zhu ◽  
Liuyi Dang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Ribosomal Proteins ◽  
Regulatory Networks ◽  
Mitochondrial Protein ◽  
Tissue Array ◽  
Colon Cancer Cells ◽  
Hub Proteins

Colon cancer is one of the most lethal malignancies worldwide. Berberine has been found to exert potential anti-colon cancer activity in vitro and in vivo, although the detailed regulatory mechanism is still unclear. This study aims to identify the underlying crucial proteins and regulatory networks associated with berberine treatment of colon cancer by using proteomics as well as publicly available transcriptomics and tissue array data. Proteome profiling of berberine-treated colon cancer cells demonstrated that among 5130 identified proteins, the expression of 865 and 675 proteins were changed in berberine-treated HCT116 and DLD1 cells, respectively. Moreover, 54 differently expressed proteins that overlapped in both cell lines were mainly involved in mitochondrial protein synthesis, calcium mobilization, and metabolism of fat-soluble vitamins. Finally, GTPase ERAL1 and mitochondrial ribosomal proteins including MRPL11, 15, 30, 37, 40, and 52 were identified as hub proteins of berberine-treated colon cancer cells. These proteins have higher transcriptional and translational levels in colon tumor samples than that of colon normal samples, and were significantly down-regulated in berberine-treated colon cancer cells. Genetic dependency analysis showed that silencing the gene expression of seven hub proteins could inhibit the proliferation of colon cancer cells. This study sheds a light for elucidating the berberine-related regulatory signaling pathways in colon cancer, and suggests that ERAL1 and several mitochondrial ribosomal proteins might be promising therapeutic targets for colon cancer.

scholarly journals Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p

2020 ◽  
Author(s):  
Shiue-Wei Lai ◽  
Ming-Yao Chen ◽  
Ming-Shou Hsieh ◽  
Ting-Yi Huang ◽  
Chi-Tai Yeh ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Cell Lines ◽  
Distant Metastasis ◽  
Colony Formation ◽  
Cancer Metastasis ◽  
Lovo Cell ◽  
Promoting Effect

Abstract Background: Late-stage colon cancer remains a treatment challenge in clinical settings because of the development of drug resistance and distant metastasis. Nevertheless, the mechanisms through which colon cancer cells acquire the ability to metastasize are complicated and require more research.Methods: Bioinformatic analysis was performed to determine gene associated with exosomal lncRNA PVT1/VEGFA axis of colon cancer patients. Biological importance of exosomal lncRNA PVT1/VEGFA axis was investigated in vitro (HCT116 and LoVo cell lines) and in vivo (PDX mouse model) through knockdown (siPVT1) and overexpression (add exosomes from sera of distant metastasis patients). PVT1/VEGFA axis related protein expression in and cell lines were investigated through RT-qPCR, immunoblotting, and immunohistochemistry analysis. Colony formation Assay, cell invasion, migration, and tumorsphere-formation assay were used to explore possible molecular mechanism. Results: First, using public databases, we demonstrated that PVT1 overexpression is associated with poor prognosis and increased metastatic markers, such as vascular endothelial growth factor A (VEGFA) and epidermal growth factor receptor (EGFR). This finding was then validated in a small cohort of patients with colon cancer, where increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. Notably, serum exosomes from patients with metastatic (M-exo) colon cancer were enriched with PVT1 and VEGFA and increased both migratory and invasive abilities in colon cancer cell lines when cocultured. This metastasis-promoting effect was accompanied by an increased expression of Twist1, Vimentin, and MMP2. Notably, M-exo promoted metastatic incidence in patient-derived xenograft mice. In vitro silencing of PVT1 led to decreased colon tumorigenic properties, including colony formation, tumorsphere formation, and metastatic potential. Further analysis revealed that miR-152-3p has multiple targets, including PVT1, VEGFA, and EGFR. Increased miR-152-3p resulted in decreased tumorigenesis, and the reverse was true when the miR-152-3p level was decreased.Conclusion: In conclusion, we provided evidence regarding the role of exosomal PVT1 in promoting metastasis in colon cancer through its association with EGFR and VEGFA expression. PVT1 and VEGFA are both targets of miR-152-3p, and this regulatory pathway could be explored for drug and prognostic biomarker development.

scholarly journals Challenges in Quantifying Cytosine Methylation in the HIV Provirus

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sarah A. LaMere ◽  
Antoine Chaillon ◽  
Christina Huynh ◽  
Davey M. Smith ◽  
Sara Gianella
Keyword(s):  
Dna Methylation ◽  
Transcriptional Repression ◽  
Cytosine Methylation ◽  
Pcr Amplification ◽  
Sampling Bias ◽  
Epigenetic Mechanism ◽  
Persons Living With Hiv ◽  
Integration Sites

ABSTRACT DNA methylation is an epigenetic mechanism most commonly associated with transcriptional repression. While it is clear that DNA methylation can silence HIV proviral expression in in vitro latency models, its correlation with HIV persistence and expression in vivo is ambiguous, particularly in persons living with HIV (PLWH) receiving antiretroviral therapy (ART). Several factors potentially contribute to discrepancies between results in the literature, including differences in integration sites, functional proviral load, sampling bias, and stochastic PCR amplification. Recent studies into genomic features of cytosine methylation sites in mammalian genes offer potentially significant insights into this mechanism. Here, we discuss the importance of these factors in the context of the HIV.

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