Runt-related Transcription Factor 1 (RUNX1T1) Suppresses Colorectal Cancer Cells Through Regulation of Cell Proliferation and Chemotherapeutic Drug Resistance

Alfayez, Musaad; Vishnubalaji, Radhakrishnan; Alajez, Nehad M.

doi:10.21873/anticanres.11096

Cited by 17 publications

(23 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also discovered somatic alterations in genes likely associated with tumor invasiveness and progression that are enriched in RCC compared to LCC (all p<0.04) but not rectal cancers (all p> 0.05): RELN,[22] MAP2,[23] NCAM1,[24] and RUNX1T1. [25] This discrepancy may be due to sample size differences (RCC n = 142, rectal cancer n = 89). Altogether, these genes are mutated in 37% of RCC (52/142) versus 10% of LCC (15/156) and showed a tendency towards mutual exclusivity (S3 Fig).…”

Section: Resultsmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

View full text Add to dashboard Cite

To understand the molecular differences between right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer, we analyzed colorectal tumors at the DNA, RNA, miRNA and protein levels using previously sequenced data from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center. Clonal evolution analysis identified the same tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor dynamics and selection of downstream mutations were distinct in all three anatomical locations, with some similarities noted between LCC and rectal cancer. We found a potentially targetable alteration APC R1450* specific to RCC that has not been previously described. Differential gene expression analysis revealed multiple genes within the homeobox, G-protein coupled receptor binding and transcription regulation families were dysregulated in RCC, LCC, and rectal cancers and may have a pathological role in these cancers. Further, using a novel in silico proteomic analytic tool developed by our research group, we found distinct central or hub proteins with unique interactomes in each location. Protein expression signatures were not necessarily concordant with the tumor profiles obtained at the DNA and RNA levels, underscoring the relevance of post-transcriptional events in defining the biology of these cancers beyond molecular changes at the DNA and/or RNA level. Ultimately, not only tumor location and the respective genomic profile but also protein-protein interactions will need to be taken into account to improve treatment outcomes of colorectal cancers. Further studies that take into account the alterations found in this study may help in developing more tailored, and perhaps more effective, treatment strategies.Author summaryPatients with right-sided colon cancer (RCC) has a worse prognosis compared to left-sided colon cancer (LCC). Recent data has also shown that wild-type RAS metastatic RCC’s have poor outcomes when treated with the combination of chemotherapy and anti-EGFR therapy compared to LCC and rectal cancers. Therefore, There is an urgent unmet need to understand the molecular differences between RCC, LCC, and rectal cancers. In this study, we demonstrate clonal evolutionary trajectory and the order of mutations in RCC, LCC, and rectal cancers are distinct with some similarities between LCC and rectal cancers. The order of the mutations that lead to the acquisition of crucial driver alterations may have prognostic and therapeutic implications. We also discovered a novel targetable alteration, APC R1450* to be significantly enriched in early, late and metastatic RCC but not in LCC and rectal cancers. Amazingly, proteomic signatures were discordant with DNA and RNA levels. These distinct differences in DNA, RNA and post-transcriptional events may contribute to their unique clinicopathological features.Conflict of Interest StatementAshiq Masood Advisory board and speaker Bureau Bristol-Myers Squibb and Boehringer IngelheimJanakiraman Subramanian Advisory board - Astra Zeneca, Pfizer, Boehringer Ingelheim, Alexion, Paradigm, Bristol-Myers Squibb Speakers Bureau - Astra Zeneca, Boehringer Ingelheim, Lilly Research Support - Biocept and ParadigmArif Hussain Advisory board – Novartis, Bayer, Astra Zeneca Consultant – Bristol-Myers-Squibb All other authors have no conflict of interest.

show abstract

Section: Resultsmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Our results predict that miR-15a may delay the aging process of nerve cells by regulating a signal pathway which has never been discovered before, thereby promoting nerve cells development to malignant proliferating cells. RUNX1T1 has the ability to inhibit the growth of tumor cells (Alfayez et al, 2016) and can be used to predict cancer metastasis based on its reduced expression (Nasir et al, 2011). Researchers considered RUNX1T1 as a prognostic biomarker for CNS tumors (Liang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Investigation of miRNA and mRNA Co-expression Network in Ependymoma

Liu

Dong

Mei

et al. 2020

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Ependymoma (EPN) is a rare primary tumor of the central nervous system (CNS) that affects both children and adults. Despite the definition and classification of distinct molecular subgroups, there remains a group of EPNs with a balanced genome, which makes it difficult to predict a prognosis of patients with EPN. The role of miRNA-mRNA network on EPN is still poorly understood. We assessed the involvement of miRNA-mRNA pairs in EPN by applying a weighted co-expression network analysis (WGCNA) approach. Using whole genome expression profile analysis followed by functional enrichment, we detected hub genes involved in active proliferation and DNA replication of nerve cells. Key genes including CYP11B1, KRT33B, RUNX1T1, SIK1, MAP3K4, MLANA, and SFRP5 identified in co-expression networks were regulated by miR-15a and miR-24-1. These seven miRNA-mRNA pairs were considered to influence not only pathways in cancer and tumor suppression process, but also MAPK, NF-kappaB, and WNT signaling pathways which were associated with tumorigenesis and development. This study provides a novel insight into potential diagnostic biomarkers of EPN and may have value in choosing therapeutic targets with clinical utility.

show abstract

“…The FTO regulated alternative splicing of RUNX1T1 further modulates preadipocyte differentiation [53] More RUNX1T1 is suggested to regulate pancreas development by regulating pancreatic polypeptide and Ghrelin expression [54]. In pathological condition, RUNX1T1 is shown to promote microglial proliferation by regulating CDK4 [55], but represses the proliferation and increases 5-flurouracil (5-FU) sensitivity in a colon cancer cell line (HCT116) [56]. These findings suggest pleiotropic effects of RUNX1T1 on different cells during development and disease progression.…”

Section: Discussionmentioning

confidence: 99%

Endothelial angiogenesis is directed by RUNX1T1-regulated VEGFA, BMP4 and TGF-β2 expression

Liao¹,

Chang

Chang³

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

Tissue angiogenesis is intimately regulated during embryogenesis and postnatal development. Defected angiogenesis contributes to aberrant development and is the main complication associated with ischemia-related diseases. We previously identified the increased expression of RUNX1T1 in umbilical cord blood-derived endothelial colony-forming cells (ECFCs) by gene expression microarray. However, the biological relevance of RUNX1T1 in endothelial lineage is not defined clearly. Here, we demonstrate RUNX1T1 regulates the survival, motility and tube forming capability of ECFCs and EA.hy926 endothelial cells by loss-and gain-of function assays, respectively. Second, embryonic vasculatures and quantity of bone marrow-derived angiogenic progenitors are found to be reduced in the established Runx1t1 heterozygous knockout mice. Finally, a central RUNX1T1-regulated signature is uncovered and VEGFA, BMP4 as well as TGF-β2 are demonstrated to mediate RUNX1T1-orchested angiogenic activities. Taken together, our results reveal that RUNX1T1 serves as a common angiogenic driver for vaculogenesis and functionality of endothelial lineage cells. Therefore, the discovery and application of pharmaceutical activators for RUNX1T1 will improve therapeutic efficacy toward ischemia by promoting neovascularization.

show abstract

Runt-related Transcription Factor 1 (RUNX1T1) Suppresses Colorectal Cancer Cells Through Regulation of Cell Proliferation and Chemotherapeutic Drug Resistance

Abstract: Our data revealed a novel role for RUNX1T1 as a tumor-suppressor gene in CRC through modulation of multiple cellular pathways.

Cited by 17 publications

References 11 publications

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Investigation of miRNA and mRNA Co-expression Network in Ependymoma

Endothelial angiogenesis is directed by RUNX1T1-regulated VEGFA, BMP4 and TGF-β2 expression

Contact Info

Product

Resources

About