Abstract
The endogenous PP2A inhibitor SET Nuclear Proto-Oncogene (SET) has been reported to play oncogenic roles and determines poor outcomes in colorectal cancer (CRC). Our group previously showed that miR-199b is deregulated in metastatic CRC, and reduced the cell viability and enhanced the sensitivity of CRC cells to standard induction chemotherapy drugs, mainly through direct negative SET regulation. Clinically, miR-199b downregulation was identified as the molecular mechanism responsible for SET overexpression in around half of metastatic CRC patients. However, the potential clinical value of miR-199b in early-stage CRC remains totally unknown. Thus, here we explored the expression levels of this microRNA in a cohort of 171 early-stage CRC patients using real-time polymerase chain reactions. MiR-199b downregulation was found in 21.6% of cases (37 out of 171) and was significantly associated with those patients with a worse Eastern Cooperative Oncology Group (ECOG) status (p = 0.045). Moreover, miR-199b downregulation predicted shorter overall (p < 0.001) and progression-free survival (p = 0.015). As expected, we next immunohistochemically analyzed SET, observing that it was significantly associated with miR-199b in our cohort. However, multivariate analyses showed that miR-199b was an independent biomarker of poor outcomes in early-stage CRC with a predictive value stronger than SET. In conclusion, our results highlight the potential clinical usefulness of miR-199b and suggest that it could represent a novel molecular target in this disease.
Highlights
Colorectal cancer (CRC) represents the most frequent gastrointestinal cancer and one of the major causes of morbidity and mortality worldwide; it is the second-most common cause of cancer-related deaths, with around 900,000 deaths annually
MiR-199b has been largely reported as a tumor suppressor that is commonly downregulated in several types of human cancers [9,10,11,12,13,14,15,16,17,18,19], only a few studies about miR-199b in CRC have been published to date
We observed that miR-199b was downregulated in 37 out of 171 cases (21.6%), and this alteration was associated with a worse Eastern Cooperative Oncology Group (ECOG) performance status (45.9% versus 19.7%, p = 0.045)
Summary
Colorectal cancer (CRC) represents the most frequent gastrointestinal cancer and one of the major causes of morbidity and mortality worldwide; it is the second-most common cause of cancer-related deaths, with around 900,000 deaths annually. This inhibition is due to the sequence complementarily binding through the “seed region” of the miR, consisting of 7–8 nucleotides located at the 5’ end, to the 3 ́ untranslated region (3 ́UTR) of the mRNA target, and leading to its degradation or its transcriptional blocking Their roles in human cancer have been largely reported since miRs function as regulators of signaling pathways that are crucial for the tumor cell and are involved in proliferation, apoptosis, or cell differentiation. Our group confirmed that miR-199b downregulation has a predictive value regarding responses to neoadjuvant chemoradiotherapy (CRT) in LARC This observation was probably due to the deregulation of the miR-199b/SET signaling axis since both miR-199b and SET were found to regulate the 5-FU resistance phenotype [25]. It remains to be determined whether miR-199b expression levels have clinical and therapeutic relevance in the subgroup of early-stage CRC patients
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