MicroRNA-425-5p Expression Affects BRAF/RAS/MAPK Pathways In Colorectal Cancers

Abstract

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.

RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

“…CRC is a common malignancy of the human digestive system and the third most common cause of cancer‐related deaths worldwide (Angius et al, 2019; Hasakova et al, 2019). Despite the advances in CRC therapies, there are still no effective therapies for CRC treatment in clinic due to the resistance generated by CRC cells to the traditional therapies (Khoshinani et al, 2017; Yin et al, 2017).…”

“…Colorectal cancer (CRC) is a leading cause of cancer death worldwide and a common cancer of the human digestive system (Angius et al, 2019; Hasakova, Reis, Vician, Zeman, & Herichova, 2019), which can seriously degrade the quality of life. Currently, the traditional therapies, such as surgical resection (Ali et al, 2018), chemotherapy (Kim, 2015), radiotherapy (Li, Dong, et al, 2019), and combined therapy (Ma, Xu, Song, Gao, & Wang, 2017) are used for CRC treatment.…”

miR-425-5p Acts as a Molecular Marker and Promoted Proliferation, Migration by Targeting RNF11 in Hepatocellular Carcinoma

“…As a functional microRNA, miR-425-5p plays different roles in tumors [ 31 – 33 ]. Recently, a study reported that miR-425-5p targeted genes are involved in the EGFR tyrosine kinase inhibitor resistance pathway, and miR-425-5p might act as an oncogene to participate in the pathogenesis of KRAS-mutated CRC [ 34 ]. miR-425-5p as a tumor suppressor gene is low expressed in prostate cancer and can affect the sensitivity of prostate cancer to cisplatin through the action of GSK3 β and Wnt/ β -catenin signaling pathways [ 35 ].…”

LncRNA GAS5 sponges miR‐362‐5p to promote sensitivity of thyroid cancer cells to 131I by upregulating SMG1

“…MicroRNAs (miRNAs) are involved in the regulation of biological processes and miRNA deregulation is implicated in tumor progression, which could be potentially therapeutic targets. 10 Certain miRNAs such as miR-335-5p 11 and miR-429 12 were involved in TC. MiR-362-5p is a miRNA usually functioning as an oncogene in human cancers, 13,14 while its role in TC progression and interaction between GAS5 and miR-362-5p remains to be further investigated.…”