MicroRNA-199b Deregulation Shows a Strong SET-Independent Prognostic Value in Early-Stage Colorectal Cancer

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.

Validation of microRNA-199b as A Promising Predictor of Outcome and Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer Patients

“…However, other studies in the literature have demonstrated that miR-199b increases 5-FU sensitivity of CRC cells through the regulation of the SIRT1/CREB/KISS1 as well as DDR1/JAG 1 signaling pathways [ 27 , 28 ]. Therefore, these observations could explain that this alteration serves as a marker of poor outcome in CRC independently of SET [ 30 ], and are in concordance with our results showed here about the clinical impact of miR-199b as a predictor of pathological response to neoadjuvant CRT in LARC patients.…”

“…These results would suggest that there are no differences in the clinical impact of LARC patients by age. Therefore, the differences previously described in early stage CRC [ 30 ] could be higher in the subgroup of colon cancer compared to rectal cancer patients. This issue needs to be clarified in forthcoming studies with series including colon and rectal cancer patients and analyses of them separately.…”

“…Here, we have observed miR-199b downregulated in 22.2% of cases, which is concordant with the prevalence described in our previous work with LARC patients (26.4%) [ 34 ], and differences could be probably due to the low number of LARC cases analyzed in that work ( n = 110) compared to the current study ( n = 185). Moreover, we had reported a prevalence of 21.6% and 24.7% in early stage and metastatic CRC patients [ 30 , 31 ], respectively. In both studies, patients were stratified by the site of primary tumor and miR-199b downregulation was found in 20% of rectum tumors vs. 26.4% of colon tumors in patients with metastatic disease, and in 18.6% vs. 22% in patients with localized disease at diagnosis.…”

“…As an important consideration, the potential relevance of the patient age as a parameter that could affect the prognostic impact of miR-199b had not been previously evaluated in LARC. However, several works in the literature with localized and metastatic CRC patients have shownthat miR-199b downregulation only achieve statistical significance as predictor of shorter progression-free survival in the subgroup of patients younger than 70 years [ 30 , 31 ]. Of note, we analyzed here the prognostic impact of miR-199b expression after stratifying our cohort by age, and observed that both subgroups of younger and elderly patients had similar statistical significance in the survival analyses performed ( Figure 2 ).…”

“…Thus, this miR has been reported to control CRC distant metastasis progression through the CREB/KISS1 [ 27 ] and DDR1/JAG1 [ 28 ] signaling pathways. In addition, our group described that miR-199b directly targets SET, a potent endogenous inhibitor of the tumor suppressor PP2A [ 29 ], thereby controlling the activation status of the SET/PP2A axis in CRC, and that its downregulation determines poor prognosis in both localized and metastatic CRC patients [ 30 , 31 ]. It has also been reported that the transcription factor E2F7 reduced the expression of miR-199b by binding to the miR-199b promoter, upregulating USP47 and MAPK, leading to an increase on the proliferation, invasion and migration abilities of colon cancer cells [ 32 ].…”