MicroRNA-425-5p Expression Affects BRAF/RAS/MAPK Pathways In Colorectal Cancers
MicroRNA-425-5p Expression Affects BRAF/RAS/MAPK Pathways In Colorectal Cancers
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DOI：
10.7150/ijms.35269
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发表时间：
2019-01-01
影响因子：
3.6
通讯作者：
De Miglio, Maria Rosaria
中科院分区：
文献类型：
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作者：
Angius, Andrea;Pira, Giovanna;De Miglio, Maria Rosaria
结直肠癌（CRC）是全球癌症死亡的主要原因，并且约20%在诊断时是转移性的并且不可治疗。转移性患者中的抗EGFR治疗由肿瘤组织中KRAS突变的存在引起。KRAS野生型CRC患者对西妥昔单抗或帕尼单抗联合化疗的阳性应答率约为70%。miRNAs是肿瘤学中很有前途的标记物，可以提高我们对CRC患者发病机制和耐药性的认识。这类分子代表了一个机会，为发展的miRNA为基础的战略，以克服无效的抗EGFR therapy.We进行了整合分析的miRNA表达谱之间的KRAS突变型CRC和KRAS野生型CRC和配对正常结肠组织（NCT）。我们发现，与KRAS野生型CRC和NCT相比，KRAS突变型CRC中miR-425- 5 p过表达，并证明miR-425- 5 p对参与细胞增殖、迁移、侵袭、凋亡分子网络的靶基因发挥调节作用。这些表观遗传机制可能是KRAS突变型CRC与KRAS野生型CRC相比具有强侵袭性的原因。我们证明了一些miR-425- 5 p靶向基因参与EGFR酪氨酸激酶抑制剂耐药途径，表明基于miR-425- 5 p的治疗可能在靶向KRAS驱动的CRC方面具有强大的潜力。此外，我们通过比较CRC与NCT，证实了miR-31- 5 p、miR-625- 5 p和miR-579在肿瘤发生中的作用。我们的结果强调，miR-425- 5 p可能作为癌基因参与KRAS突变CRC的发病机制，并有助于增加该亚类CRC的侵袭性，控制复杂的分子网络。
Colorectal cancer (CRC) is a leading cause of cancer death worldwide and about 20% is metastatic at diagnosis and untreatable. The anti-EGFR therapy in metastatic patients is led by the presence of KRAS-mutations in tumor tissue. KRAS-wild-type CRC patients showed a positive response rate of about 70% to cetuximab or panitumumab combined with chemotherapy. MiRNAs are promising markers in oncology and could improve our knowledge on pathogenesis and drug resistance in CRC patients. This class of molecules represents an opportunity for the development of miRNA-based strategies to overcome the ineffectiveness of anti-EGFR therapy.We performed an integrative analysis of miRNA expression profile between KRAS-mutated CRC and KRAS-wildtype CRC and paired normal colic tissue (NCT). We revealed an overexpression of miR-425-5p in KRAS-mutated CRC compared to KRAS-wild type CRC and NCT and demonstrated that miR-425-5p exerts regulatory effects on target genes involved in cellular proliferation, migration, invasion, apoptosis molecular networks. These epigenetic mechanisms could be responsible of the strong aggressiveness of KRAS-mutated CRC compared to KRAS-wildtype CRC. We proved that some miR-425-5p targeted genes are involved in EGFR tyrosine kinase inhibitor resistance pathway, suggesting that therapies based on miR-425-5p may have strong potential in targeting KRAS-driven CRC. Moreover, we demonstrated a role in the oncogenesis of miR-31-5p, miR-625-5p and miR-579 by comparing CRC versus NCT.Our results underlined that miR-425-5p might act as an oncogene to participate in the pathogenesis of KRAS-mutated CRC and contribute to increase the aggressiveness of this subcategory of CRC, controlling a complex molecular network.