Microsatellite Status and IκBα Expression Levels Predict Sensitivity to Pharmaceutical Curcumin in Colorectal Cancer Cells

Lu, Lixuan; Przybylla, Randy; Shang, Yongpeng; Dai, Meng; Krohn, Mathias; Krämer, Oliver H.; Mullins, Christina Susanne; Linnebacher, Michael

doi:10.3390/cancers14041032

Cited by 6 publications

(5 citation statements)

References 64 publications

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“…The highest incidence and mortality rates of 52.3% and 54.2% were observed in Asia (9). The 5year prevalence has been recorded in 5,253,335 persons across all populations (10). Furthermore, CRC is more common in men (23.4) than women (16.2) according to agestandardized incidence rates calculated per 100,000 persons (11).…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

Modekurty

2024

Preprint

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Background: Oxaliplatin is the standard treatment option for colorectal cancer (CRC) which is one of the most prevalent forms of cancer. However, patients suffer either treatment discontinuation or adverse post-treatment life quality due to Oxaliplatin-induced peripheral neuropathy. Methods: Our study has comprehensively explored the molecular mechanisms underlying Oxaliplatin-induced peripheral neuropathy via an extensive literature survey and identified multiple genes that may contribute to neuropathy and neurotoxicity. In addition to that, the publicly available bulk transcriptomic data of Illumina HiSeq 2500 platform, comprising the CRC tissue of 18 individuals' tumor and adjacent normal tissue was processed to identify differentially expressed genes (DEGs). Moreover, the single-cell RNA sequencing data of 10X genomics comprising normal and tumor tissues was subjected to analysis using Seurat and sctype R packages to uncover the cancer cells associated DEGs. Functional and pathway enrichment analysis was conducted using the Genecodis4 web-based tool. Next, RNA-seq data of CRC cell lines treated with Oxaliplatin compared with normal individuals, was also processed and DEGs were determined to validate the inhibition of a curated list of neuropathy-associated genes. Results: From literature and database searches, a total of 1367 genes, including ion channel genes, normal sensory neuron-associated genes, and axon-excitability-related genes were collected that are either reported to be or may be contributing to neuropathy among cancer survivors upon oxaliplatin administration. The bulk transcriptomic data analysis revealed 715 DEGs and single-cell analysis uncovered 2,854 DEGs. Identified upregulated genes from single-cell data analysis, such as LGALS4, SPINK4, TFF3, REG4, and REG1A were found to be associated with tumor proliferation via epithelial-mesenchymal transitions, oxidative stress, dysregulated immune system, and inflammation which can be utilized as potential targets to devise novel therapeutic strategies for CRC treatment. Furthermore, many proteins involved in axon-excitability (NGF, SOD1, ROBO1, CNTNAP2, CNTNAP2, and KCNMB1), normal sensory neuron (SOX10, APOE, SST, S1PR1, and KCND3), voltage-gated sodium (SCNN1B, SCNN1G, SCNN1A, SCN1B, and SCN2B), calcium (CACNA2D2, CACNA1A, CACNA1C, CACNA1E, and CACNA1F), and potassium channels (KCND3, KCNMB1, KCNMA1, KCNJ2, and KCNN4) showed downregulation due to the oxaliplatin administration in CRC cell lines and their inhibition may have led to neuropathy which needs further validations. Conclusion: Our study uncovers the downregulation of multiple genes upon oxaliplatin administration leading to neuropathy development and also elucidates potential therapeutic targets for better prognosis of CRC.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

Modekurty

2024

Preprint

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“…Another difference is the microsatellite stability; in fact, as reported by Yashiro et al, LoVo has an MSI phenotype, while HT-29 cells do not [84]. Some of these features may influence the response to SFN treatments, as in the case of other phytochemical compounds such as curcumin, the activity of which may be affected by the microsatellite status [85].…”

Section: Discussionmentioning

confidence: 97%

MicroRNAs miR-584-5p and miR-425-3p Are Up-Regulated in Plasma of Colorectal Cancer (CRC) Patients: Targeting with Inhibitor Peptide Nucleic Acids Is Associated with Induction of Apoptosis in Colon Cancer Cell Lines

Gasparello

Papi

Zurlo

et al. 2022

Cancers

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Liquid biopsy has dramatically changed cancer management in the last decade; however, despite the huge number of miRNA signatures available for diagnostic or prognostic purposes, it is still unclear if dysregulated miRNAs in the bloodstream could be used to develop miRNA-based therapeutic approaches. In one author’s previous work, nine miRNAs were found to be dysregulated in early-stage colon cancer (CRC) patients by NGS analysis followed by RT-dd-PCR validation. In the present study, the biological effects of the targeting of the most relevant dysregulated miRNAs with anti-miRNA peptide nucleic acids (PNAs) were verified, and their anticancer activity in terms of apoptosis induction was evaluated. Our data demonstrate that targeting bloodstream up-regulated miRNAs using anti-miRNA PNAs leads to the down-regulation of target miRNAs associated with inhibition of the activation of the pro-apoptotic pathway in CRC cellular models. Moreover, very high percentages of apoptotic cells were found when the anti-miRNA PNAs were associated with other pro-apoptotic agents, such as sulforaphane (SFN). The presented data sustain the idea that the targeting of miRNAs up-regulated in the bloodstream with a known role in tumor pathology might be a tool for the design of protocols for anti-tumor therapy based on miRNA-targeting molecules.

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“…Investigators screened different molecular types of CRC on cell lines to find the ones with the highest sensitivity to curcumin, a natural product [ 34 ]. Most curcumin-sensitive cell lines were of the MSS molecular type, and they had high baseline levels of the IκBα protein.…”

Section: Discussionmentioning

confidence: 99%

“…Most curcumin-sensitive cell lines were of the MSS molecular type, and they had high baseline levels of the IκBα protein. Conversely, curcumin-resistant cell lines were mainly of the MSI type, and showed low baseline IκBα levels [ 34 ]. This suggests curcumin could be useful for treatment or prevention of MSS CRC, and there are ongoing efforts to increase its bioavailability [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Association of Microsatellite Instability and Gene Expression Profile in Colorectal Carcinoma and Potential Implications for Therapy

Kibriya,

Jasmine,

Khamkevych

et al. 2024

Medicina

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Background and Objective: In sporadic colorectal carcinomas (CRC), microsatellite instability (MSI) pathways play important roles. Previously, we showed differences in DNA methylation patterns in microsatellite stable (MSS) colorectal carcinomas and MSI-CRC. In the current study, we explore the similarities and differences in gene expression profiles in MSS and MSI at the gene level and at the pathway level to better understand CRC pathogenesis and/or the potential for therapeutic opportunities. Material and Methods: Seventy-one CRC patients (MSI = 18, MSS = 53) were studied. Paired tumor and adjacent normal tissues were used for genome-wide gene expression assays. Result: At the gene level, we compared the list of differentially expressed genes (fold change (FC) ≥ 3 and FDR < 0.05) in tumor tissues compared to corresponding normal tissue in CRC patients with MSI tumors (190 genes) and MSS tumors (129 genes). Of these, 107 genes overlapped. The list of genes that were differentially expressed in MSI tumors only showed enrichment predominantly in two broad categories of pathways—(a) Inflammation-related pathways including the interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, chemokine signaling, nuclear factor kappa B (NFκB) signaling, and cytokine-cytokine interactions, and (b) metabolism-related pathways, including retinol metabolism, steroid hormone biosynthesis, drug metabolism, pentose and glucoronate interconversions, and ascorbate and aldarate metabolism. The genes in inflammation-related pathways were up-regulated whereas genes in metabolism-related pathways were down-regulated in MSI tumor tissue. Pathway-level analysis also revealed similar results confirming the gene enrichment findings. For example, the 150 genes involved in the IL-17 signaling pathway were on average up-regulated by 1.19 fold (CI 1.16–1.21) in MSI compared to 1.14 fold (CI 1.13–1.16) in MSS patients (interaction p = 0.0009). Conclusions: We document an association between MSI status and differential gene expression that broadens our understanding of CRC pathogenesis. Furthermore, targeting one or more of these dysregulated pathways could provide the basis for improved therapies for MSI and MSS CRC.

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Microsatellite Status and IκBα Expression Levels Predict Sensitivity to Pharmaceutical Curcumin in Colorectal Cancer Cells

Cited by 6 publications

References 64 publications

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

MicroRNAs miR-584-5p and miR-425-3p Are Up-Regulated in Plasma of Colorectal Cancer (CRC) Patients: Targeting with Inhibitor Peptide Nucleic Acids Is Associated with Induction of Apoptosis in Colon Cancer Cell Lines

Association of Microsatellite Instability and Gene Expression Profile in Colorectal Carcinoma and Potential Implications for Therapy

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