RUNX2 and Cancer

Abstract

Runt-related transcription factor 2 (RUNX2) is critical for the modulation of chondrocyte osteoblast differentiation and hypertrophy. Recently discovered RUNX2 somatic mutations, expressional signatures of RUNX2 in normal tissues and tumors, and the prognostic and clinical significance of RUNX2 in many types of cancer have attracted attention and led RUNX2 to be considered a biomarker for cancer. Many discoveries have illustrated the indirect and direct biological functions of RUNX2 in orchestrating cancer stemness, cancer metastasis, angiogenesis, proliferation, and chemoresistance to anticancer compounds, warranting further exploration of the associated mechanisms to support the development of a novel therapeutic strategy. In this review, we focus mainly on critical and recent research developments, including RUNX2's oncogenic activities, by summarizing and integrating the findings on somatic mutations of RUNX2, transcriptomic studies, clinical information, and discoveries about how the RUNX2-induced signaling pathway modulates malignant progression in cancer. We also comprehensively discuss RUNX2 RNA expression in a pancancer panel and in specific normal cell types at the single-cell level to indicate the potential cell types and sites for tumorigenesis. We expect this review to shed light on the recent mechanistical findings and modulatory role of RUNX2 in cancer progression and provide biological information that can guide new research in this field.

Keywords: RUNX2; cancer progression; prognosis.

Figure 1

The isoform view of human RUNX2. The red and green arrowheads show the positions of the stop codon and transcription start site, respectively. In addition, the matched protein domains in each isoform are marked in orange. Runt: Runt domain. RunxI: Runx inhibition domain. The information is based on the data adapted with permission from Ingenuity Pathway Analysis. Copyright Year 2023, QIAGEN.

Figure 2

A pancancer study addressing whole genome data reveals the sites and types of RUNX2 mutations. Gray indicates the truncating mutations (putative driver) including nonsense, nonstop, frameshift deletion, and frameshift insertion. Light green indicates the missense mutations. Runt: Runt domain. RunxI: Runx inhibition domain. Data were adapted with permission from cBioPortal (https://docs.cbioportal.org/user-guide/faq/#can-i-use-figures-from-the-cbioportal-in-my-publications-or-presentations) accessed on: 21 February 2023.

Figure 3

Human RUNX2 RNA distribution in single cells across different cell types. The RUNX2 level was measured by scRNA-seq in different tissues. The RNA expression levels are visualized at the single-cell level by UMAP plot. Data were adapted with permission from HPA (https://www.proteinatlas.org/about/licence#citation_guidelines_for_the_human_protein_atlas, accessed on: 21 February 2023).

Figure 4

Relative RUNX2 expression across pan-normal cell types. RUNX2 RNA levels were measured by scRNA-seq in 192 specific cell type clusters. nTPM: TPM values of all samples were normalized separately using the trimmed mean of M values (TMM) to allow for between-sample comparisons and normalized transcript expression values. Data were adapted with permission from HPA (https://www.proteinatlas.org/about/licence#citation_guidelines_for_the_human_protein_atlas, accessed on: 21 February 2023).

Figure 5

RUNX2 RNA-seq data in 17 cancer types (TCGA) were re-analyzed. These transcript expression data were obtained by RNA-Seq analyses based on the data retrieved from the TCGA database and were normalized and used to assess relative RUNX2 expression in various types of cancers. Data are shown as the median number of fragments per kilobase per million (FPKM). Normal distribution in the dataset is represented by the box plots, and the points represent the data of outliers if the expression levels are below or above 1.5 times the interquartile range. Data were adapted with permission from HPA (https://www.proteinatlas.org/about/licence#citation_guidelines_for_the_human_protein_atlas, accessed on: 21 February 2023).

Figure 6

Representative scheme of RUNX2′s modulations to hallmarks of cancer.