Transcriptome analysis of human colorectal cancer biopsies reveals extensive expression correlations among genes related to cell proliferation, lipid metabolism, immune response and collagen catabolism

Xu, Lai; Wang, Rong; Ziegelbauer, Joseph M.; Wu, Wells W.; Shen, Rong; Juhl, Hartmut; Zhang, Yaqin; Pelosof, Lorraine; Rosenberg, Amy S.

doi:10.18632/oncotarget.20345

Cited by 27 publications

(23 citation statements)

References 78 publications

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“…The striking emergence of IFNs and IRGs as important players in the progression and the resistance of cancer cells have gained interest, especially in the context of CRC, since increasing evidence reveals that affected tissue or cells from patients exhibit overexpression of IRGs when compared to normal samples. For example, IRGs such as CMPK2, 20 , 21 IFITM1, 22 - 26 IFITM2, 22 , 27 IFITM3, 22 , 28 IRF2, 29 ISG15, 30 MX1, 31 , 32 and PLSCR1, 33 have been proposed as markers for diagnosis, aggressiveness and prognosis of CRC. Interestingly, the treatment of HT-29 cells with avicequinone B diminished the expression of several CRC-related IRGs (CMPK2, IFIT1, IFITM1, IFITM2, IFITM3, ISG15, and PLSCR1) together with other cancer-related IRGs (IFI27, IFIT2, IFIT3, IRF7, IRF9, and STAT1).…”

Section: Resultsmentioning

confidence: 99%

Transcriptome Changes in Colorectal Cancer Cells upon Treatment with Avicequinone B

et al. 2020

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Purpose: Naphtho[2,3-b]furan-4,9-dione (Avicequinone B), a natural naphthoquinone isolated from the mangrove tree Avicennia alba, is recognized as a valuable synthetic precursor with anti-proliferative effect. However, the molecular mechanism involved in its bioactivity has not been investigated. This study aimed to determine the selectivity of avicequinone B against cancer cells and the transcriptomic changes induced in colorectal cancer (CRC). Methods: The cytotoxic effect against adenocarcinoma-derived cells or fibroblasts was evaluated using MTT assay. In addition, CRC cells were treated with avicequinone B in different settings to evaluate colony-forming ability, cell cycle progression, apoptosis/necrosis induction, and transcriptome response by RNA-seq. Results: Avicequinone B effectively reduced the viability of breast, colorectal, and lung adenocarcinoma cells with IC50 lower than 10 μM, while fibroblasts were less affected. The induction of G2/M arrest and necrosis-like cell death were observed in avicequinone B-treated HT-29 cells. Furthermore, RNA-seq revealed 490 differentially expressed genes, highlighting the reduction of interferon stimulated genes and proliferative signaling pathways (JAK-STAT, MAPK, and PI3K-AKT), as well as the induction of ferroptosis and miR-21 expression. Conclusion: In short, these results demonstrated the therapeutic potential of avicequinone B and paved the foundation for elucidating its mechanisms in the context of CRC.

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Section: Resultsmentioning

confidence: 99%

Transcriptome Changes in Colorectal Cancer Cells upon Treatment with Avicequinone B

et al. 2020

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“…Clinical and histopathological characteristics of the patients as well as tumor location are summarized in Additional file 1: Table S1. Among these 80 tumor pairs, 79 pairs were sequenced except the T7/N7 pair [10–12].…”

Section: Methodsmentioning

confidence: 99%

“…Paired-end sequencing was carried out on HiSeq 2500 sequencer (Illumina, San Diego, CA, USA) for 100 × 2 cycles. For each sample, we obtained ~ 50 million 100-bp reads that passed preset filtering parameters [10–12].…”

Section: Methodsmentioning

confidence: 99%

Novel reference genes in colorectal cancer identify a distinct subset of high stage tumors and their associated histologically normal colonic tissues

Xu¹,

Luo²,

Wang³

et al. 2019

BMC Med Genet

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Background Reference genes are often interchangeably called housekeeping genes due to 1) the essential cellular functions their proteins provide and 2) their constitutive expression across a range of normal and pathophysiological conditions. However, given the proliferative drive of malignant cells, many reference genes such as beta-actin ( ACTB ) and glyceraldehyde-3-phosphate-dehydrogenase ( GAPDH ) which play critical roles in cell membrane organization and glycolysis, may be dysregulated in tumors versus their corresponding normal controls Methods Because Next Generation Sequencing (NGS) technology has several advantages over hybridization-based technologies, such as independent detection and quantitation of transcription levels, greater sensitivity, and increased dynamic range, we evaluated colorectal cancers (CRC) and their histologically normal tissue counterparts by NGS to evaluate the expression of 21 “classical” reference genes used as normalization standards for PCR based methods. Seventy-nine paired tissue samples of CRC and their patient matched healthy colonic tissues were subjected to NGS analysis of their mRNAs. Results We affirmed that 17 out of 21 classical reference genes had upregulated expression in tumors compared to normal colonic epithelial tissue and dramatically so in some cases. Indeed, tumors were distinguished from normal controls in both unsupervised hierarchical clustering analyses (HCA) and principal component analyses (PCA). We then identified 42 novel potential reference genes with minimal coefficients of variation (CV) across 79 CRC tumor pairs. Though largely consistently expressed across tumors and normal control tissues, a subset of high stage tumors (HSTs) as well as some normal tissue samples (HSNs) located adjacent to these HSTs demonstrated dysregulated expression, thus identifying a subset of tumors with a potentially distinct and aggressive biological profile. Conclusion While classical CRC reference genes were found to be differentially expressed between tumors and normal controls, novel reference genes, identified via NGS, were more consistently expressed across malignant and normal colonic tissues. Nonetheless, a subset of HST had profound dysregulation of such genes as did many of the histologically normal tissues adjacent to such HSTs, indicating that the HSTs so distinguished may have unique biological properties and that their histologically normal tissues likely harbor a small population of microscopically undetected but metabolically active tumors. Electronic supplementary material The online version of this article (10.1186/s12881-019-0867-y) contains supplementary material, which is available to authorized users.

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“…Cufflinks V.2.2.1 was used to assemble the transcriptome based on the hg19 reference annotation, and Cuffquan/Cuffnorm (part of Cufflinks) were used in calculating relative abundance of each transcript reported as FPKM. Gene co-expression analyses were carried by Partek NGS & microarray data analysis software (25,28,29). Integrated Discovery (DAVID) v6.7 (https://david.ncifcrf.gov/) was used for biological pathway determination and Cytoscape (2.8.2) was used for gene coexpression networks construction.…”

Section: Sequencing Data Analysismentioning

confidence: 99%

“…A total of 25,761 genes were detected. Because genes with higher FPKM values may have greater biological impact, we focused on genes with FPKM > 1 (25,28). Ten thousand two hundred fifty-five genes (40% of total genes) had an average FPKM > 1 and differential expression between tumors and normal controls (False Discovery Rate (FDR) < 0.05 in ANOVA).…”

Section: Initial Expression Landscape Of Crcmentioning

confidence: 99%

NGS Evaluation of Colorectal Cancer Reveals Interferon Gamma Dependent Expression of Immune Checkpoint Genes and Identification of Novel IFNγ Induced Genes

Pelosof

Wang

et al. 2020

Front. Immunol.

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To evaluate the expression of immune checkpoint genes, their concordance with expression of IFNγ, and to identify potential novel ICP related genes (ICPRG) in colorectal cancer (CRC), the biological connectivity of six well documented ("classical") ICPs (CTLA4, PD1, PDL1, Tim3, IDO1, and LAG3) with IFNγ and its co-expressed genes was examined by NGS in 79 CRC/healthy colon tissue pairs. Identification of novel IFNγ-induced molecules with potential ICP activity was also sought. In our study, the six classical ICPs were statistically upregulated and correlated with IFNγ, CD8A, CD8B, CD4, and 180 additional immunologically related genes in IFNγ positive (FPKM > 1) tumors. By ICP co-expression analysis, we also identified three IFNγ-induced genes [(IFNγ-inducible lysosomal thiol reductase (IFI30), guanylate binding protein1 (GBP1), and guanylate binding protein 4 (GBP4)] as potential novel ICPRGs. These three genes were upregulated in tumor compared to normal tissues in IFNγ positive tumors, co-expressed with CD8A and had relatively high abundance (average FPKM = 362, 51, and 25, respectively), compared to the abundance of the 5 well-defined ICPs (Tim3, LAG3, PDL1, CTLA4, PD1; average FPKM = 10, 9, 6, 6, and 2, respectively), although IDO1 is expressed at comparably high levels (FPKM = 39). We extended our evaluation by querying the TCGA database which revealed the commonality of IFNγ dependent expression of the three potential ICPRGs in 638 CRCs, 103 skin cutaneous melanomas (SKCM), 1105 breast cancers (BC), 184 esophageal cancers (ESC), 416 stomach cancers (STC), and 501 lung squamous carcinomas (LUSC). In terms of prognosis, based on Pathology Atlas data, correlation of GBP1 and GBP4, but not IFI30, with 5-year survival rate was favorable in CRC, BC, SKCM, and STC. Thus, further studies defining the role of IFI30, GBP1, and GBP4 in CRC are warranted.

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Transcriptome analysis of human colorectal cancer biopsies reveals extensive expression correlations among genes related to cell proliferation, lipid metabolism, immune response and collagen catabolism

Cited by 27 publications

References 78 publications

Transcriptome Changes in Colorectal Cancer Cells upon Treatment with Avicequinone B

Transcriptome Changes in Colorectal Cancer Cells upon Treatment with Avicequinone B

Novel reference genes in colorectal cancer identify a distinct subset of high stage tumors and their associated histologically normal colonic tissues

NGS Evaluation of Colorectal Cancer Reveals Interferon Gamma Dependent Expression of Immune Checkpoint Genes and Identification of Novel IFNγ Induced Genes

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