Abstract
Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment.
Highlights
Colorectal cancer (CRC) is a gastrointestinal cancer with the highest incidence rate and is the fourth leading cause of cancer-related death worldwide [1], with rectal cancer accounting for approximately30% of all colorectal tumors [2]
We investigate the role of miR-199b determining resistance to 5-fluorouracil treatment and analyze its potential clinical impact in the subgroup of locally advanced rectal cancer (LARC) patients
5-FU-induced in both SW480 and HT-29 cells in comparison with those cells transfected with a negative control antitumor properties in both SW480 and HT-29 cells in comparison with those cells transfected with miRNA (Figure 1A)
Summary
Colorectal cancer (CRC) is a gastrointestinal cancer with the highest incidence rate and is the fourth leading cause of cancer-related death worldwide [1], with rectal cancer accounting for approximately30% of all colorectal tumors [2]. The guidelines of the National Comprehensive Cancer Network recommend a multidisciplinary approach consisting of 5-fluorouracil (5-FU)-based preoperative CRT followed by total mesorectal excision (TME) surgery that represents the treatment of choice for locally advanced rectal cancer (LARC) [3,4]. 5-FU is more used, the oral 5-FU prodrug capecitabine has recently been defined as a useful alternative option [5]. This therapeutic regimen has improved the management of LARC patients and was established after several studies demonstrating that alone [6,7].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
