# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
### Secondary Resistance
#### 1.3.6 ATP-Binding Cassette (ABC) Transporters  
ATP-binding cassette (ABC) transporters form one of the most prominent protein families with diverse physiologic functions. These transporters comprise a ubiquitous superfamily of integral membrane proteins responsible for the ATP-powered translocation of many substrates across membranes. ABC-mediated drug efflux is the primary mechanism of multidrug resistance (MDR). The MDR-related transporters in the ABC transporter family include P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRPs) [PERSON] et al. (2019). ABC transporter overexpression is a significant cause of MDR [PERSON] et al. (2019). In a study by [PERSON] et al., the author demonstrated that heme oxygenase 1 (HMOX1) reduces the sensitivity of HCC cells to sorafenibb via regulation of the ABC transporter's expression [PERSON] et al. (2019). A study by [PERSON] et al. investigated the role of BCRP/ABCG2 in HCC sensitivity to sorafenibb and showed that BCRP/ABCG2 mediated sorafenibib's efflux and made it resistant. The author also demonstrated that the cortreatment with a BCRP/ABCG2 inhibitor significantly increased the sorafenibb cytotoxicity in HCC cells [PERSON] et al. (2019). Figure 1 illustrates the transport of sorafenibb and the pathways involved. The dysregulated overexpression of ABC transporters mediated by lncRNAs in chemoresistant cancers is significant and cannot be overlooked. Understanding the underlying mechanisms may provide a theoretical basis for the clinical therapy of HCC and RC-CRecent approaches for gene therapy targeting lncRNAs to suppress ABC transporters show promise in reversing HCC and RCC chemoresistance [105]. HULC lncRNA has been reported to correlate with Sirt1 protein levels in human HCC tissues positively and can be used in RCCfor stabilizing Sirt1 protein and triggering autophagy to attenuate the chemosensitivity of HCC and other cancer cells. In oxaliplatin-resistant HCC cells (Huh7/O.X.A. and HepG2/OXA), NR2F1-AS1 knockdown reduces the mRNA expression levels of drug resistance-related genes, including MDR1, MRP5, and LRP1, indicating that NR2F1-AS1 silencing could decrease oxaliplatin resistance. Additionally, the ABCC1 protein is upregulated in oxaliplatin-resistant HCC cells. ABCC1, a known multidrug resistance-related protein, serves as an effective indicator of drug resistance. Both NR2F1-AS1 and ABCC1 are upregulated in these cultured oxaliplatin-resistant HCC cells, suggesting that ABCC1 might function as a direct target of NR2F1-AS1 in regulating oxaliplatin resistance [106; 107]. LncRNAs such as MALAT-1, HULC, and H19 have been implicated in human HCC, RCC, and other cancers; however, the functional contributions of these and other lncRNA genes remain largely unknown [108]. MALAT1 was demonstrated to act as a competing endogenous RNA (ceRNA) for miR-216a-5p, thereby preventing the microRNA from inhibiting ABCG2 expression. The upregulation of ABCG2 due to MALAT1  
Figure 1: Sorafenib, an anticancer drug, is transported into the cell through SLC proteins (OCT1 and FKSG16) and undergoes metabolism via CYP3A4 (phase 1) and phase 2 U.D.P. glucuronosyl-transferase 1A9 (UGT1A9) to form the M1-M8 metabolites. Among the metabolites of sorafenib, M2, M4 (demethylation), and M5 (oxidative metabolite) were found to inhibit vascular endothelial growth factor receptors (VEGFRs). Sorafenib resistance: On the left side of the figure, sorafenib, an anticancer drug, is taken up into the cell primarily through the solute carrier (SLC proteins) and the organic cation transporter (OCT1). Once inside, sorafenib undergoes metabolism via CYP3A4 (phase 1) and phase 2 U.D.P. glucuronosyltransferase 1A9 (UGT1A9) to form the M1-M6 metabolites, including sorafenibb glucuronide. These metabolites, particularly M2, can undergo glucuronidation to further reduce their activity. Sorafenib and its metabolites are also effluxed out of the cell by ABC transporters, including BCRP and MRP2, which contribute to drug re-sistance.