Cristóbal Ion, Santos Andrea, Rubio Jaime, Caramés Cristina, Zazo Sandra, Sanz-Álvarez Marta, Luque Melani, Madoz-Gúrpide Juan, Rojo Federico, García-Foncillas Jesús
Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain.
Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain.
Cancers (Basel). 2021 Oct 5;13(19):5003. doi: 10.3390/cancers13195003.
The absence of established predictive markers with value to anticipate response to neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)-199b has been reported to play a key role determining 5-FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5-FU resistant phenotype. Moreover, miR-199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR-199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR-199b expression was quantified by real-time-PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size ( = 0.026) and positive lymph node after CRT ( = 0.005), and higher pathological stage ( = 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT ( = 0.004). Moreover, the subgroup of cases with low miR-199b levels had a markedly shorter overall ( < 001) and event-free survival ( < 0.001), and multivariate analyses showed that miR-199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence ( = 0.004). Finally, we compared miR-199b expression profiles in a set of cases with pre and post-treatment samples available, observing that only a minimal response leads to miR-199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.
缺乏能够预测新辅助5-氟尿嘧啶（5-FU）为基础的放化疗（CRT）疗效的既定预测标志物，是当前局部晚期直肠癌（LARC）面临的一项重大挑战。据报道，肿瘤抑制性微小RNA（miR）-199b通过调控多种信号通路，在决定大肠癌细胞对5-FU的敏感性方面发挥关键作用，并已成为克服5-FU耐药表型的新型分子靶点。此外，miR-199b下调被描述为一种常见改变，提示LARC患者对术前CRT无反应，但这一问题需要在独立的更大队列中得到证实。在此，我们评估miR-199b在LARC中的临床影响，并进行额外分析以进一步阐明其作为该疾病新型标志物的潜在相关性。因此，通过实时PCR对185例LARC患者队列中的miR-199b表达进行定量分析，发现该miR在22.2%的病例中表达下调，且与更大的肿瘤大小（P = 0.026）、CRT后阳性淋巴结（P = 0.005）以及更高的病理分期（P = 0.004）显著相关。值得注意的是，这种改变显示出对新辅助CRT病理反应不佳具有强大的独立预测价值（P = 0.004）。此外，miR-199b水平低的病例亚组的总生存期（P < 0.001）和无事件生存期明显更短（P < 0.001），多变量分析表明miR-199b失调是LARC患者预后的独立预测指标。有趣的是，这种miR的预后影响在年轻和老年患者中均非常显著，并且在确定患者复发方面非常有效（P = 0.004）。最后，我们比较了一组有治疗前和治疗后样本的病例中的miR-199b表达谱，观察到只有极小的反应会导致miR-199b水平升高，这进一步表明其作为LARC管理中有前景的标志物和新型分子靶点具有潜在的临床和治疗相关性。
