CRC is the third most diagnosed cancer in the US with the second-highest mortality rate. A multi-modality approach with surgery/chemotherapy is used in patients with early stages of colon cancer. Radiation therapy is added to the armamentarium in patients with locally advanced rectal cancer. While some patients with metastatic CRC are cured, the majority remain incurable and receive palliative chemotherapy as the standard of care. Recently, immune checkpoint blockade has emerged as a promising treatment for many solid tumors, including CRC with microsatellite instability. However, it has not been effective for microsatellite stable CRC. Here, main mechanisms of immunosuppression in CRC will be discussed, aiming to provide some insights for restoring immunosurveillance to improve treatment efficacy in CRC.

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

The EVI1 gene encodes for a transcription factor with two zinc finger domains and is transcriptionally activated in a subset of myeloid leukemias. In leukemia, the transcriptional activation of EVI1 usually results from chromosomal rearrangements. Besides leukemia, EVI1 has also been linked to solid tumors including breast cancer, lung cancer, ovarian cancer and colon cancer. The MDS1/EVI1 gene is encoded by the same locus as EVI1. While EVI1 functions as a transcription repressor, MDS1/EVI1 acts as a transcription activator. The fusion protein encoded by the AML1/MDS1/EVI1 chimeric gene, resulting from chromosomal translocations in a subset of chronic myeloid leukemia, exhibits a similar function to EVI1. EVI1 has been shown to regulate cell proliferation, differentiation and apoptosis, whereas the functions of MDS1/EVI1 and AML1/MDS1/EVI1 remain elusive. In this review, we summarize the genetic structures, biochemical properties and biological functions of these proteins in cancer.

With advances in next generation sequencing (NGS) technologies, efforts have been made to develop personalized medicine, targeting the specific genetic makeup of an individual. Somatic or germline DNA Polymerase epsilon (PolE) mutations cause ultramutated (>100 mutations/Mb) cancer. In contrast to mismatch repair-deficient hypermutated (>10 mutations/Mb) cancer, PolE-associated cancer is primarily microsatellite stable (MSS) In this article, we provide a comprehensive review of this PolE-associated ultramutated tumor. We describe its molecular characteristics, including the mutation sites and mutation signature of this type of tumor and the mechanism of its ultramutagenesis. We discuss its good clinical prognosis and elucidate the mechanism for enhanced immunogenicity with a high tumor mutation burden, increased neoantigen load, and enriched tumor-infiltrating lymphocytes. We also provide the rationale for immune checkpoint inhibitors in PolE-mutated tumors.

MicroRNAs (miRNAs) are a family of short, noncoding RNAs that can regulate gene expression levels of over half of the human genome. Previous studies on the role of miRNAs in cancer showed overall widespread downregulation of miRNAs as a hallmark of human cancer, though individual miRNAs can be both tumor suppressive and oncogenic, and cancer genes are speculated to be more targeted by miRNA. However, the extents to which oncogenes and tumor suppressor genes (TSG) are controlled by miRNA have not been compared. To achieve this goal, we constructed lists of oncogenes and TSGs and compared them with each other, and with the whole protein-coding gene population, in terms of miRNA binding sites distribution and expression level changes upon genetic disruption of miRNA production. As expected, the results show that cancer gene mRNAs anchor more miRNA binding sites, and are under a higher degree of miRNA-mediated repression at both mRNA abundance and translation efficiency levels than the whole protein-coding gene population. Importantly, on average, TSG mRNAs are more highly targeted and regulated by miRNA than oncogene mRNAs. To the best of our knowledge, this is the first comparison of miRNA regulation of oncogenes and TSGs.