Novel Genetic and Epigenetic Biomarkers of Prognostic and Predictive Significance in Stage II/III Colorectal Cancer

Luo, Xiao-Jing; Zhao, Qi; Liu, Jia; Zheng, Jia-Bo; Qiu, Miaozhen; Ju, Huai-Qiang; Xu, Rui‐Hua

doi:10.1016/j.ymthe.2020.12.017

Cited by 69 publications

(54 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic alterations include chromosomal instability (CIN), microsatellite instability (MSI), and mutations of some critical driver genes, such as Kirsten rat sarcoma viral oncogene (KRAS) and its downstream target B-Raf proto-oncogene (BRAF), adenomatous polyposis coli (APC), and tumor protein p53 (TP53) 3 , 4 . Epigenetic alterations mainly refer to the CpG island methylation phenotype (CIMP) 5 . Following the implementation of early screening and genomic profiling to detect somatic variants, an increasing number of CRC patients have achieved early diagnosis and targeted treatment 1 .…”

Section: Introductionmentioning

confidence: 99%

Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer

et al. 2021

View full text Add to dashboard Cite

Background: Tumor metastasis of colorectal cancer (CRC) is the main cause of death in most patients and the major difficulty in comprehensive CRC treatment. Circular RNAs (circRNAs) affect many biological functions in solid tumors. However, their mechanisms in CRC metastasis remain unclear. Methods: RNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed circRNAs between CRC tissues and adjacent normal tissues. CCK-8, cell migration and wound healing assays were performed to determine the functions of circRHOBTB3 in cell proliferation and metastasis. RNA pulldown and RNA immunoprecipitation assays were performed to verify the interaction between circRHOBTB3 and the HuR (ELAVL1) protein. Further RNA-seq and rescue experiments were applied to search for the downstream target. We also conducted a mouse xenograft model to elucidate the effect of circRHOBTB3 on cancer metastasis in vivo . Results: We identified circRHOBTB3 which is markedly downregulated in CRC tissues and cell lines. Furthermore, lower circRHOBTB3 levels were significantly associated with advanced clinical stages and greater risk of metastases. Overexpression of circRHOBTB3 suppresses tumor metastasis in CRC cells. Mechanistically, circRHOBTB3 binds to HuR, which is a ubiquitously expressed and functional RNA-binding protein (RBP) in CRC development, and promotes β-Trcp1-mediated ubiquitination of HuR. Normally, HuR binds to the 3'UTR of target mRNAs to facilitate their stabilization, whereas the interaction between circRHOBTB3 and HuR degrades HuR to reduce the expression level of the downstream target PTBP1. Furthermore, overexpressed circRHOBTB3 suppresses lung metastases in vivo , and this effect can be partly reversed by PTBP1 overexpression. In addition, the transcription of circRHOBTB3 can be improved by both FUS and ADARB2 in CRC cells. Conclusions: Our findings indicate that circRHOBTB3 exerts suppressive effects on CRC aggressiveness through the HuR/PTBP1 axis.

show abstract

Section: Introductionmentioning

confidence: 99%

Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…However, the prognosis of patients with CRC is often less optimistic than expected, mainly due to 5-FU resistance (4,5). Several studies have shown that approximately half of patients receiving chemotherapy for stage II and III CRC eventually develop chemotherapy resistance and disease recurrence (6)(7)(8). Therefore, identifying potential therapeutical targets has become an imperative need for CRC patients.…”

Section: Introductionmentioning

confidence: 99%

Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer

Pan

Wang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Emerging evidence suggests that hypermethylation of HOXD10 plays an important role in human cancers. However, the biological and clinical impacts of HOXD10 overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of HOXD10 in paired cancer and normal tissues (n = 42) by using pyrosequencing, followed by validation of the methylation status of HOXD10 from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of HOXD10 was characterized in cell lines. We further evaluated the effects of HOXD10 and its targets on chemoresistance in our established resistant cell lines and clinical cohort (n = 66). HOXD10 was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, HOXD10 acts as a tumor suppressor gene, in which HOXD10-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the HOXD10 promoter, and demethylation by 5-Aza-2′-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce HOXD10 expression. HOXD10 regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of HOXD10 in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that HOXD10 is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of HOXD10 activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).

show abstract

“…Advancements in genetic research have allowed more insights into the mechanism behind this malignant disease and may provide more advanced and accurate ways to evaluate the prognosis of HCC patients. Genetic biomarkers have been identified for cancer detection, risk assessment, and prognosis prediction in multiple types of cancer, including brain cancer, colorectal cancer, and prostate cancer 30–32 . Genetic tools can also help in cancer prevention and treatment by providing precision therapeutic targets, which have been proven to be effective in breast cancer treatment 33,34 .…”

Section: Discussionmentioning

confidence: 99%

“…Genetic biomarkers have been identified for cancer detection, risk assessment, and prognosis prediction in multiple types of cancer, including brain cancer, colorectal cancer, and prostate cancer. 30 , 31 , 32 Genetic tools can also help in cancer prevention and treatment by providing precision therapeutic targets, which have been proven to be effective in breast cancer treatment. 33 , 34 In this study, we identified five target genes ( UBE2S , PTTG1 , CDC20 , SOCS2 , and DNASE1L3 ) closely correlated with the prognosis of HCC patients through the integration of gene expression profiles from multiple databases.…”

Section: Discussionmentioning

confidence: 99%

Prognostic evaluation and immune infiltration analysis of five bioinformatic selected genes in hepatocellular carcinoma

Lai

Tai

Jiang

et al. 2021

J Cellular Molecular Medi

View full text Add to dashboard Cite

Despite the development in hepatocellular carcinoma (HCC) treatment in recent years, the therapeutic outcome of HCC remains unfavourable. This study examines the prognosis of HCC from a genetic level using clinical databases and single‐cell data to identify genes with a high prognostic value. Three up‐regulated genes (UBE2S, PTTG1, and CDC20) and two down‐regulated genes (SOCS2 and DNASE1L3) in HCC tissues were identified. Various analyses confirmed its correlation with tumour stage (p < 0.01) and patient survival time (log‐rank p < 0.001). Immune analysis, single‐cell analysis, and gene set enrichment analysis (GSEA) were employed to provide insight on how they affect cancer progression, and we observed a close relation between these genes and tumour immune infiltration. Eventually, we constructed a risk score system that risk score = (0.0465) × UBE2S + (0.1851) × CDC20 + (−0.0461) × DNASE1L3 + (−0.2279) × SOCS2 (5‐year area under curve = 0.706). The risk score system may serve as an effective novel prognostic system for HCC patients. This study might provide novel ideas for prognostic or therapeutic biomarkers for HCC.

show abstract

Novel Genetic and Epigenetic Biomarkers of Prognostic and Predictive Significance in Stage II/III Colorectal Cancer

Cited by 69 publications

References 119 publications

Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer

Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer

Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer

Prognostic evaluation and immune infiltration analysis of five bioinformatic selected genes in hepatocellular carcinoma

Contact Info

Product

Resources

About