Intratumoral heterogeneity for inactivating frameshift mutation of CUX1 and SIRT1 genes in gastric and colorectal cancers

Jo, Yun Sol; Kim, Min Sung; Yoo, Nam Jin; Lee, Sug Hyung

doi:10.5114/pjp.2017.71534

Cited by 3 publications

(2 citation statements)

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“…Sirtuin 1 (SIRT1) is one of the early studied members of sirtuin family and is considered as a key regulator of various biological processes, especially in cancer. It has reported that SIRT1 is related to the tumorigenesis of gastric and colorectal cancers [2], the mitochondrial apoptosis of prostate cancer [3], and the prognosis of breast cancer [4]. Importantly, SIRT1 is confirmed to be involved in the tumorigenesis [5], proliferation [6], metastasis [7], and chemical resistant [8] of HCC which hinted its potential role in liver cancer.…”

Section: Introductionmentioning

confidence: 97%

HBx mediated Increase of SIRT1 Contributes to HBV-related Hepatocellular Carcinoma Tumorigenesis

Wang¹,

Cheng²,

Chen³

2020

Int. J. Med. Sci.

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Objective: Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related deaths worldwide, and chronic hepatitis B virus (HBV) infection is strongly associated with HCC development, but the pathogenesis of HBV-related HCC remains obscure. Sirtuin 1 (SIRT1) has been implicated to enhance the replication of HBV and to promote the tumorigenesis of HCC. In this study, we aim to investigate the functional role of SIRT1 on HBV viral protein and HBV-induced HCC. Methods: Tumorous liver tissues from patient diagnosed with HBV-related HCC were collected and further divided into two groups (with or without metastasis). Then, the mRNA and protein level of SIRT1 in those tissues were detected by real time PCR and Western blot, respectively. Meanwhile, the protein level of epithelial-mesenchymal transition (EMT) relative markers in those tissues was determined by Western blot. Furthermore, the expression of SIRT1 in HBV-expressing HCC cells was examined. Next, the relationship between viral proteins and SIRT1 expression were determined by real time PCR and Western blot. In addition, the potential role of HBx-upregulated SIRT1 in HCC proliferation, migration and invasion were analyzed by cell viability assays, cell proliferation assay, wound healing assay, transwell assay and Western blot. Results: In this study, we found that the expression of SIRT1 was obviously increased in patients with metastasis compared to the patients without metastasis. Consistently, the expression of SIRT1 was also upregulated in HBV-expressing HCC cells compared to the controls. Further investigation showed that viral protein HBx was responsible for the elevated SIRT1 in HBV-expressing HCC cells. Meanwhile, the expression of HBx could be upregulated by SIRT1. Additionally, functional studies showed that HBx-elevated SIRT1 could promote HCC cell proliferation, migration and invasion. Importantly, HBx induced HCC proliferation and migration could be suppressed by Nicotinamide in a dose dependent manner. Conclusions: Our findings uncovered the positive role of SIRT1 in HBx-mediated tumorigenesis which implicated the potential role of SIRT1 in HBV-related HCC treatment.

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Section: Introductionmentioning

confidence: 97%

HBx mediated Increase of SIRT1 Contributes to HBV-related Hepatocellular Carcinoma Tumorigenesis

Wang¹,

Cheng²,

Chen³

2020

Int. J. Med. Sci.

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“…CUX1 shares four similar DNA-binding domain architectures, including a CUT homeodomain and three CUT repeats (CR1, CR2, CR3), which are evolutionarily and functionally conserved from metazoans to humans (Ludlow et al, 1996;Vanden Heuvel et al, 2005;Kedinger et al, 2009). As a major member of the CUX family, it is involved in multiple biological processes including cell differentiation, proliferation, cell cycle regulation, tissue development, and double strand breaks (DSBs) repair response, besides, CUX1 expression was abnormally elevated in many malignant tumors and was implicated in tumorigenesis (Ramdzan and Nepveu, 2014;Wong et al, 2014;Jo et al, 2017). Many lines of evidence have indicated that overexpression of CUX1 was present in various types of cancers, such as melanoma, pancreatic cancer, multiple myeloma, and breast cancer (Fan et al, 2014;Vadnais et al, 2014;Krug et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

CUX1 Facilitates the Development of Oncogenic Properties Via Activating Wnt/β-Catenin Signaling Pathway in Glioma

Fěng

Zhao

Zhou

et al. 2021

Front. Mol. Biosci.

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Background: Homeobox cut like 1 (CUX1), which often presents aberrated expression in many cancer cells, exerts a crucial role in tumorigenesis. Evidence describing CUX1 in gliomagenesis is scarce, and the effects of CUX1 on the Wnt/β-catenin pathway have not been reported. Our study aimed to explore the biological functions and molecular mechanisms involved in CUX1 activity in glioma.Methods: Datasets for bioinformatics analysis were obtained from the GEO, TCGA, CGGA, GTEX and CCLE databases. qRT-PCR, western blotting (WB), and immunohistochemistry (IHC) assays were used to investigate the expression patterns of CUX1 among glioma and brain tissues. CUX1 knockdown and overexpression vectors were transfected into glioma cell lines, the CCK-8, clone formation assay, wound healing, Transwell assay, and flow cytometry were performed to detect changes in cell viability, invasiveness, and the cell cycle. WB and immunofluorescence (IF) assays were used to explore changes in cell cycle-related and Wnt/β-catenin signaling protein levels.Results: Overexpression of CUX1 was identified in glioma tissues, and especially in glioblastoma (GBM), when compared to normal controls and correlated with poor prognosis. In comparison with untreated cells, TJ905 glioma cells overexpressing CUX1 showed higher proliferation and invasion abilities and S phase cell-cycle arrest, while the knockdown of CUX1 suppressed cell invasive ability and induced G1 phase arrest. Active Wnt/β-catenin signaling was enriched and clustered in a CUX1-associated GSEA/GSVA analysis. IF and WB assays indicated that CUX1 regulated the distribution of Axin2/β-catenin in glioma cells and regulated the expression of proteins downstream of the Wnt/β-catenin signaling pathway, suggesting that CUX1 served as an upstream positive regulator of the Wnt/β-catenin pathway. Finally, the knockdown of Axin2 or β-catenin could reverse the tumor-promoting effects caused by CUX1 overexpression, suggesting that CUX1 induced gliomagenesis and malignant phenotype by activating the Wnt/β-catenin signaling pathway.Conclusion: Our data suggested that the transcription factor CUX1 could be a novel therapeutic target for glioma with gene therapy.

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Impact of mini-driver genes in the prognosis and tumor features of colorectal cancer samples: a novel perspective to support current biomarkers

Segura

Sotomayor

Román

et al. 2023

PeerJ

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Background Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, and its development is associated with the gains and/or losses of genetic material, which leads to the emergence of main driver genes with higher mutational frequency. In addition, there are other genes with mutations that have weak tumor-promoting effects, known as mini-drivers, which could aggravate the development of oncogenesis when they occur together. The aim of our work was to use computer analysis to explore the survival impact, frequency, and incidence of mutations of possible mini-driver genes to be used for the prognosis of CRC. Methods We retrieved data from three sources of CRC samples using the cBioPortal platform and analyzed the mutational frequency to exclude genes with driver features and those mutated in less than 5% of the original cohort. We also observed that the mutational profile of these mini-driver candidates is associated with variations in the expression levels. The candidate genes obtained were subjected to Kaplan–Meier curve analysis, making a comparison between mutated and wild-type samples for each gene using a p-value threshold of 0.01. Results After gene filtering by mutational frequency, we obtained 159 genes of which 60 were associated with a high accumulation of total somatic mutations with Log2 (fold change) > 2 and p values < 10−5. In addition, these genes were enriched to oncogenic pathways such as epithelium-mesenchymal transition, hsa-miR-218-5p downregulation, and extracellular matrix organization. Our analysis identified five genes with possible implications as mini-drivers: DOCK3, FN1, PAPPA2, DNAH11, and FBN2. Furthermore, we evaluated a combined classification where CRC patients with at least one mutation in any of these genes were separated from the main cohort obtaining a p-value < 0.001 in the evaluation of CRC prognosis. Conclusion Our study suggests that the identification and incorporation of mini-driver genes in addition to known driver genes could enhance the accuracy of prognostic biomarkers for CRC.

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Intratumoral heterogeneity for inactivating frameshift mutation of CUX1 and SIRT1 genes in gastric and colorectal cancers

Cited by 3 publications

References 11 publications

HBx mediated Increase of SIRT1 Contributes to HBV-related Hepatocellular Carcinoma Tumorigenesis

HBx mediated Increase of SIRT1 Contributes to HBV-related Hepatocellular Carcinoma Tumorigenesis

CUX1 Facilitates the Development of Oncogenic Properties Via Activating Wnt/β-Catenin Signaling Pathway in Glioma

Impact of mini-driver genes in the prognosis and tumor features of colorectal cancer samples: a novel perspective to support current biomarkers

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