MicroRNA-19b Plays a Key Role in 5-Fluorouracil Resistance and Predicts Tumor Progression in Locally Advanced Rectal Cancer Patients

Abstract

The standard clinical management of locally advanced rectal cancer (LARC) patients includes neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) followed by mesorectal excision. MicroRNA (miR)-19b expression levels in LARC biopsies obtained from initial colonoscopy have recently been identified as independent predictors of both patient outcome and pathological response to preoperative CRT in this disease. Moreover, it has been discovered that this miR increases its expression in 5-FU resistant colon cancer cells after 5-FU exposure. Despite the fact that these observations suggest a functional role of miR-19b modulating 5-FU response of LARC cells, this issue still remains to be clarified. Here, we show that downregulation of miR-19b enhances the antitumor effects of 5-FU treatment. Moreover, ectopic miR-19b modulation was able to restore sensitivity to 5-FU treatment using an acquired resistant model to this compound. Notably, we also evaluated the potential clinical impact of miR-19b as a predictive marker of disease progression after tumor surgery resection in LARC patients, observing that miR-19b overexpression significantly anticipates patient recurrence in our cohort (p = 0.002). Altogether, our findings demonstrate the functional role of miR-19b in the progressively decreasing sensitivity to 5-FU treatment and its potential usefulness as a therapeutic target to overcome 5-FU resistance, as well as its clinical impact as predictor of tumor progression and relapse.

Deregulation of the miR-19b/PPP2R5E Signaling Axis Shows High Functional Impact in Colorectal Cancer Cells

“…We first explored how miR-19b modulates cell viability, which was significantly enhanced after miR-19b overexpression, and reduced when this miR was silenced (Figure 1). These findings were concordant with the observed results in our previous work when we analyzed the effect of miR-19b in determining 5-FU sensitivity [30]. As expected, PPP2R5E overexpression significantly impaired cell viability whereas its silencing led to increased cell viability (Figures S1 and S2), suggesting that miR-19b-induced effects are at least partially mediated by its role as negative PPP2R5E regulator.…”

“…In addition, miR-19b predicts shorter overall survival and metastatic progression in CRC patients [28]. In concordance, previous studies from our group showed that miR-19b is highly deregulated in LARC, and predicts both patient outcome and pathological response to neoadjuvant chemoradiotherapy (nCRT), and cancer progression in this disease, observing higher recurrence rates in patients with high miR-19b levels [29,30]. Moreover, PP2A regulatory subunit PPP2R5E was able to predict the response to nCRT in our LARC patient cohort, confirming the inverse correlation that exists between miR-19b and PPP2R5E expression in this disease [29].…”

“…Thus, we identified not only a negative correlation between miR-19b and PPP2R5E in LARC patients, but also that PPP2R5E expression was predictive of pathological response to neoadjuvant treatment in this disease [29]. Moreover, miR-19b determines 5-FU resistance and predicts tumor progression in LARC [30], but the potential role of PPP2R5E in this issue was not investigated. Thus, we analyzed the role of PPP2R5E in the previously described miR-19bmediated effects on the 5-FU response of CRC cells, and studied the functional significance of the miR-19b/PPP2R5E signaling axis in this disease.…”

Circulating Tumour Cell Associated MicroRNA Profiles Change during Chemoradiation and Are Predictive of Response in Locally Advanced Rectal Cancer

“…This finding of miR-19b and correlation with tumour response is supported by other studies in the literature, mainly in solid tissue [ 31 , 32 ]. miR-19b expression levels in LARC biopsies obtained at time of colonoscopy have been identified as an independent predictor of pathological response to preoperative chemoradiation.…”

“…miR-19b expression levels in LARC biopsies obtained at time of colonoscopy have been identified as an independent predictor of pathological response to preoperative chemoradiation. miR-19b expression increases in chemotherapy-resistant cells and downregulation of miR-19b enhances the antitumor effects of chemotherapy [ 32 ]. miR-19b was also found to be overexpressed in colorectal tissue, and indicated a poor prognosis.…”