LncRNA UCA1 mediates Cetuximab resistance in Colorectal Cancer via the MiR-495 and HGF/c-MET Pathways

Abstract

Background: Cetuximab is one of the most widely used monoclonal antibodies to treat patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC). Unfortunately, cetuximab resistance often occurs during targeted therapy. However, the underlying epigenetic mechanisms remain unclear. Our previous study demonstrated that the exosomal transfer of urothelial carcinoma-associated 1 (UCA1) confers cetuximab resistance to CRC cells. The goal of this study was to elucidate the detailed role of UCA1 in cetuximab resistance in CRC and the underlying molecular mechanism. Methods: In vitro and in vivo functional studies were performed to assess the role of UCA1 in cetuximab resistance in CRC cell lines and xenograft models. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to examine UCA1 localization and expression. Bioinformatics analysis was performed to predict the potential mechanism of UCA1, which was further validated by the dual-luciferase reporter assay and the RNA immunoprecipitation (RIP) assay. Cells treated with indicators were subjected to Cell Counting Kit-8 (CCK-8) and western blotting to investigate the role of hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition (c-MET) signalling in UCA1-mediated cetuximab resistance. Results: We showed that UCA1 decreased CRC cell sensitivity to cetuximab by suppressing apoptosis. Mechanistic studies revealed that UCA1 promoted cetuximab resistance by competitively binding miR-495 to facilitate HGF and c-MET expression in CRC cells. Moreover, HGF was shown to attenuate the cetuximab-induced inhibition of cell proliferation by activating the HGF/c-MET pathway in CRC cells. Conclusion:We provide the first evidence of a UCA1-miR-495-HGF/c-MET regulatory network involved in cetuximab resistance in CRC. Therefore, UCA1 has potential as a predictor and therapeutic target for cetuximab resistance.

Competitive endogenous RNA networks: Decoding the role of long non‐coding RNAs and circular RNAs in colorectal cancer chemoresistance

“…A recent study revealed that UCA1 enhances cetuximab resistance by targeting miR‐495 and suppressing its expression in CRC 49 . Through the use of five miRNA target identification algorithms, it was determined that hepatocyte growth factor (HGF) and c‐mesenchymal‐to‐epithelial transition (c‐MET) were targets of miR‐495 49 . c‐MET, a tyrosine kinase receptor for HGF, is notable for its capacity to induce cancer 51 .…”

“…c‐MET, a tyrosine kinase receptor for HGF, is notable for its capacity to induce cancer 51 . Moreover, HGF was found to reduce the cetuximab‐induced suppression of cell growth in CRC cells by activating the HGF/c‐MET axis 49 . The HGF/c‐MET axis has emerged as a potential therapeutic target for a variety of malignancies, including CRC, as indicated by a growing body of research 52 .…”

The Functional Role of LncRNA UCA1 in Pancreatic Cancer: a mini-review

“…A large number of lncRNAs have also been shown to induce drug resistance in cancer cells [62][63][64]. Overexpression of UCA1 has been reported to be associated with resistance to chemo-therapeutic drugs, including 5-fluorouracil, cisplatin, gemcitabine, paclitaxel, docetaxel, gefitinib, cetuximab, doxorubicin, daunorubicin, tamoxifen, temozolomide, and trastuzumab, in many kinds of tumor cells [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80]. Recently, the role of UCA1 in the chemoresistance of PaC has also been investigated.…”

Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy

“…UCA1 acts as a ceRNA to regulate the target genes expression at the post-transcriptional level [149][150][151], and it is overexpressed in CRC cells and tissues. As a sponge for miR-495, UCA1 binds and inhibits miR-495, promotes the expression of hepatocyte growth factor (HGF) and c-MET, activates the HGF/c-MET signaling pathway in CRC cells, and attenuates the Cetuximabinduced cell proliferation inhibition, thereby promoting Cetuximab resistance [32].…”

“…In addition to lncRNAs and circRNAs, ceRNAs include endogenously transcribed pseudogenes [ 29 , 31 ]. In recent years, ceRNAs have been found to be involved in tumor development, and ceRNA networks play an important role in resistance to anti-EGFR mAbs in CRC [ 30 , 32 , 33 ]. This paper mainly reviewed the lncRNAs, miRNAs, and circRNAs related to anti-EGFR mAbs resistance, and elucidated their correlation with anti-EGFR mAbs resistance for CRC and the potential mechanism, providing new methods and ideas for predicting the prognosis and treatment of CRC patients.…”