Abstract
The identification of robust prognostic markers still represents a need in locally advanced rectal cancer (LARC). MicroRNAs (miRs) have progressively emerged as promising circulating markers, overcoming some limitations that traditional biopsy comprises. Tissue miR-199b deregulation has been reported to predict outcome and response to neoadjuvant chemoradiotherapy (nCRT) in LARC, and was also found to be associated with disease progression in colorectal cancer. However, its biological and clinical relevance remains to be fully clarified. Thus, we observed here that miR-199b regulates cell migration, aggressiveness, and cell growth, and inhibits colonosphere formation and induces caspase-dependent apoptosis. Moreover, miR-199b expression was quantified by real-time PCR in plasma samples from LARC patients and its downregulation was observed in 22.7% of cases. This alteration was found to be associated with higher tumor size (p = 0.002) and pathological stage (p = 0.020) after nCRT. Notably, we observed substantially lower global miR-199b expression associated with patient downstaging (p = 0.009), as well as in non-responders compared to those cases who responded to nCRT in both pre- (p = 0.003) and post-treatment samples (p = 0.038). In concordance, we found that miR-199b served as a predictor marker of response to neoadjuvant therapy in our cohort (p = 0.011). Altogether, our findings here demonstrate the functional relevance of miR-199b in this disease and its potential value as a novel circulating marker in LARC.
Highlights
Colorectal cancer (CRC) is already the third leading cause of cancer death in the world, with rectal cancer (RC) representing almost 30% of total CRC cases, and its incidence is steadily rising in developing countries and in younger patients [1]
We aimed to investigate the functional relevance of miR-199b deregulation as an alteration that could be contributing to disease progression
These observations were confirmed in the HT-29 cell line, which showed similar regulation of its migration ability when miR-199b was overexpressed or silenced, respectively, and differences were statistically significant in both cases with this cell line (Figure 1)
Summary
Colorectal cancer (CRC) is already the third leading cause of cancer death in the world, with rectal cancer (RC) representing almost 30% of total CRC cases, and its incidence is steadily rising in developing countries and in younger patients [1]. Given the achievement of pCR in a wide range of patients undergoing nCRT and the major effects and complications of total mesorectal excision (TME) surgery, there is a growing interest in the identification of patients that could benefit from a watch and wait (W&W) clinical approach. This novel strategy could avoid surgery in around 25% of cases and supports organ preservation, avoiding unnecessary postoperative morbidity with good long-term oncological outcomes and improving quality of life in highly selected patients [6,7]. The RAPIDO and PRODIGE 23 phase III randomized clinical trials have recently shown that the addition of neoadjuvant chemotherapy to a standard short- or long-course radiation significantly decreases the risk of metastatic progression and associates with a better disease-free survival in LARC patients [8,9]
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