Loss of RUNX1 is associated with aggressive lung adenocarcinomas

Abstract

The mammalian runt-related factor 1 (RUNX1) is a master transcription factor that regulates lineage specification of hematopoietic stem cells. RUNX1 translocations result in the development of myeloid leukemias. Recently, RUNX1 has been implicated as a tumor suppressor in other cancers. We postulated RUNX1 expression may be associated with lung adenocarcinoma etiology and/or progression. We evaluated the association of RUNX1 mRNA expression with overall survival data from The Cancer Genome Atlas (TCGA), a publically available database. Compared to high expression levels, Low RUNX1 levels from lung adenocarcinomas were associated with a worse overall survival (Hazard Ratio = 2.014 (1.042-3.730 95% confidence interval), log-rank p = 0.035) compared to those that expressed high RUNX1 levels. Further immunohistochemical examination of 85 surgical specimens resected at the University of Vermont Medical Center identified that low RUNX1 protein expression was associated with larger tumors (p = 0.038). Gene expression network analysis was performed on the same subset of TCGA cases that demonstrated differential survival by RUNX1 expression. This analysis, which reveals regulatory relationships, showed that reduced RUNX1 levels were closely linked to upregulation of the transcription factor E2F1. To interrogate this relationship, RUNX1 was depleted in a lung cancer cell line that expresses high levels of RUNX1. Loss of RUNX1 resulted in enhanced proliferation, migration, and invasion. RUNX1 depletion also resulted in increased mRNA expression of E2F1 and multiple E2F1 target genes. Our data implicate loss of RUNX1 as driver of lung adenocarcinoma aggression, potentially through deregulation of the E2F1 pathway.

Long non‐coding RNA RUNX1‐IT1 plays a tumour‐suppressive role in colorectal cancer by inhibiting cell proliferation and migration

“…[9][10][11][12][13] Runt domain transcription factor (RUNX) family is mainly composed of RUNX1, RUNX2, RUNX, 14 and the functions of these three factors are slightly different. [16][17][18] LncRNA RUNX1-IT1 is the intronic transcript 1 of the RUNX1, which is also known as chromosome 21 open reading frame 96 (C21orF96). 15 Besides, RUNX1 has also been reported as a tumour suppressor in many cancers, such as gastric cancer, lung adenocarcinomas.…”

“…15 Besides, RUNX1 has also been reported as a tumour suppressor in many cancers, such as gastric cancer, lung adenocarcinomas. [16][17][18] LncRNA RUNX1-IT1 is the intronic transcript 1 of the RUNX1, which is also known as chromosome 21 open reading frame 96 (C21orF96).…”

Hub Genes of Stroke Identified by Weighted Gene Co-expression Network Analysis

“…Two key noncoding RNAs (RUNX1-IT1 and ANP32A-IT1) were identi ed as effective diagnostic genes in the present study. LncRNA RUNX1-IT1, and ANP32A-IT1 are the intronic transcript 1 from their respective genes [64,65]. RUNX1 IT1 plays a tumour suppressive role and plays aprotective role in colorectal cancer by regulating cell proliferation, migration, and apoptosis [65].…”

FOXD1 and Gal-3 Form a Positive Regulatory Loop to Regulate Lung Cancer Aggressiveness

“…The transcription factor Runx1 has been identified as being involved in Gal-3 expression [30]. However, a previous study reported that the knockdown of RUNX1 increased lung cancer cell growth and motility, and lung cancer patients with low RUNX1 exhibit a poor prognosis [28]. Intriguingly, there is no report of FOXD1 being associated with Gal-3 expression.…”

“…Extracellular Gal-3 acts as a mediator that regulates metastatic cancer processes by recognizing N-acetyllactosamine (β-galactoside)-conjugated proteins, including EGFR, integrins, TGF-β receptors, etc. [25,27,28]. For instance, the interaction of integrin β3 and Gal-3 contributes to EGFR tyrosine kinase inhibitor resistance, which facilitates lung cancer cell stemness properties and renders them more resistant to chemotherapeutic agents [29].…”