Aberrant HMGA2 Expression Sustains Genome Instability That Promotes Metastasis and Therapeutic Resistance in Colorectal Cancer

SIMPLE SUMMARY: Despite recent advances in early diagnostic and therapeutic strategies, colorectal cancer remains one of the most diagnosed and lethal cancers worldwide. Further, several patients are diagnosed at late stages with metastatic disease, ultimately limiting their therapeutic options. To better these statistics and overall patient survival, it is critical to identify and validate potential biomarkers (select genes) that contribute to colorectal cancer development (metastasis) and chemoresistance. Additionally, research has shown a clear association between genome instability, which confers an increased number of genetic alterations, and colorectal cancer. Although the aberrant expressions of various genes have been associated with early colorectal development, few have been validated as markers of metastatic disease. In this review, we highlight current research that suggests a member of the High-Mobility Group A gene family may be a potential biomarker of metastatic spread and therapeutic resistance in colorectal cancer. Further, we explain the mechanisms by which this gene, when aberrantly expressed, sustains genome instability in cancer cells that promote metastasis and chemoresistance in colorectal cancer, ultimately highlighting it as a promising biomarker that warrants further study. ABSTRACT: Colorectal cancer (CRC) is one of the most lethal cancers worldwide, accounting for nearly ~10% of all cancer diagnoses and deaths. Current therapeutic approaches have considerably increased survival for patients diagnosed at early stages; however, ~20% of CRC patients are diagnosed with late-stage, metastatic CRC, where 5-year survival rates drop to 6–13% and treatment options are limited. Genome instability is an enabling hallmark of cancer that confers increased acquisition of genetic alterations, mutations, copy number variations and chromosomal rearrangements. In that regard, research has shown a clear association between genome instability and CRC, as the accumulation of aberrations in cancer-related genes provides subpopulations of cells with several advantages, such as increased proliferation rates, metastatic potential and therapeutic resistance. Although numerous genes have been associated with CRC, few have been validated as predictive biomarkers of metastasis or therapeutic resistance. A growing body of evidence suggests a member of the High-Mobility Group A (HMGA) gene family, HMGA2, is a potential biomarker of metastatic spread and therapeutic resistance. HMGA2 is expressed in embryonic tissues and is frequently upregulated in aggressively growing cancers, including CRC. As an architectural, non-histone chromatin binding factor, it initiates chromatin decompaction to facilitate transcriptional regulation. HMGA2 maintains the capacity for stem cell renewal in embryonic and cancer tissues and is a known promoter of epithelial-to-mesenchymal transition in tumor cells. This review will focus on the known molecular mechanisms by which HMGA2 exerts genome protective functions that contribute to cancer cell survival and chemoresistance in CRC.