Guanine nucleotide-binding protein-like-3-like (GNL3L) is a crucial regulator of NF-κB signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of GNL3L tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is necessary to effectively generate therapeutic strategies for metastatic human colorectal cancer (CRC). This study aims to identify how cells acquire resistance to anticancer drugs and whether the downregulation of miR-4454 is associated with the progression of CRC. Here, we have shown that the overexpression of miR-4454 in resistant tumors is a crucial precursor for the posttranscriptional repression of GNL3L in human chemoresistant CRC progression, and we used doxycycline induced miR-4454 overexpression that significantly reduced tumor volume in a subcutaneous injection nude mice model. Together, these observations highlight that the downregulation of miR-4454 in resistant clones is prominently responsible for maintaining their resistance against anticancer drug therapy. Our study indicates that the development of miR-4454 as a microRNA-based therapeutic approach to silence GNL3L may remarkably reduce oncogenic cell survival that depends on GNL3L/NF-κB signaling, making miR-4454 a candidate for treating metastatic human CRC.
Keywords: GNL3L (guanine nucleotide-binding protein-like-3-like); colorectal cancer (CRC); irinotecan (CPT-11); miR-4454.