MALAT1 in colorectal cancer: Its implication as a diagnostic, prognostic, and predictive biomarker

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.

Colorectal cancer (CRC) is the second most common cause of cancer death in the United States. Every 3 years, the American Cancer Society provides an update of CRC occurrence based on incidence data (available through 2016) from population-based cancer registries and mortality data (through 2017) from the National Center for Health Statistics. In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years. The incidence rate during 2012 through 2016 ranged from 30 (per 100,000 persons) in Asian/Pacific Islanders to 45.7 in blacks and 89 in Alaska Natives. Rapid declines in incidence among screening-aged individuals during the 2000s continued during 2011 through 2016 in those aged 65 years and older (by 3.3% annually) but reversed in those aged 50 to 64 years, among whom rates increased by 1% annually. Among individuals aged younger than 50 years, the incidence rate increased by approximately 2% annually for tumors in the proximal and distal colon, as well as the rectum, driven by trends in non-Hispanic whites. CRC death rates during 2008 through 2017 declined by 3% annually in individuals aged 65 years and older and by 0.6% annually in individuals aged 50 to 64 years while increasing by 1.3% annually in those aged younger than 50 years. Mortality declines among individuals aged 50 years and older were steepest among blacks, who also had the only decreasing trend among those aged younger than 50 years, and excluded American Indians/Alaska Natives, among whom rates remained stable. Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high-quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults.