MicroRNA-19b Plays a Key Role in 5-Fluorouracil Resistance and Predicts Tumor Progression in Locally Advanced Rectal Cancer Patients.
Andrea SantosIon CristóbalJaime RubioCristina CaramésMelani LuqueMarta Sanz-ÁlvarezSandra ZazoJuan Madoz-GúrpideFederico RojoJesus García-FoncillasPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- rectal cancer
- locally advanced
- end stage renal disease
- poor prognosis
- ejection fraction
- chronic kidney disease
- newly diagnosed
- neoadjuvant chemotherapy
- squamous cell carcinoma
- prognostic factors
- peritoneal dialysis
- radiation therapy
- clinical trial
- minimally invasive
- oxidative stress
- transcription factor
- phase ii study
- lymph node
- induced apoptosis
- signaling pathway
- long noncoding rna
- cell death
- ultrasound guided
- acute coronary syndrome
- endoplasmic reticulum stress
- replacement therapy