# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
## 2 Long Noncoding RNAs (IncRNAs) in Sorafenib Resistance  
LncRNAs are critical in the sorafenib resistance in HCC. They are longer than 200 nucleotides with no protein-coding ability, and are involved in fundamental biological processes and diverse activities. They can act as a sponge for a variety of miRNAs and also interact with one or more RNA-binding proteins (RBPs) to be involved in multiple biological processes by regulating cell proliferation, apoptosis, metastasis, and invasion. LncRNAs play multifaceted roles in drug resistance across various cancers, influencing cellular processes and contributing to treatment efficacy or resistance mechanisms. Several studies have demonstrated that lncRNAs function as miRNA sponges to regulate target gene expression, mediating sorafenib resistance in HCC. In a study by [PERSON] et al., lncRNA NEAT1 targets miR-149-5p and reduces the activity of sorafenib in HCC cells. NEAT1 was inversely correlated with miR-149-5p expression. Patients with high expression of NEAT1 had worse overall survival rates [24]. In another study by [PERSON] et al., the same lncRNA targeted miR-335 (negatively regulated by NEAT1) and further suppressed the c-Met-Akt pathway, the activation of which leads to drug resistance in HCC cells [109]. [PERSON] et al. demonstrated that more significant amounts of HCC tissue contained reduced levels of this epigenetically regulated lncRNA H19. This lncRNA showed tumor-suppressive actions, and restoring H19 actions might represent an approach for future HCC therapies [110]. Another lncRNA, TUC338, was shown to play a role in the chemotherapy resistance of HCC cells in both in vitro and in vivo studies, which may be mediated by its regulation of RASAL1 expression [111]. A study by [PERSON] et al. showed how TGF\(\beta\) might contribute to altered responses to treatment by assessing the involvement and mechanistic contribution of extracellular vesicle lncRNA in mediating TGF\(\beta\)-dependent chemoresistance [112]. HOXA13, a HOX gene, is most overexpressed in HCC and is known to be directly regulated by the lncRNA HOTTIP, and high expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and increases sorafenib response in vitro models [113]. In a study by [PERSON] et al., the author showed a correlation of SNHG3 with malignant status and poor prognosis in hepatocellular carcinoma, and SNHG3 expression was directly proportional to tumor size, portal vein tumor thrombus and relapse [114]. Another study demonstrated that the knockdown of the lncRNA SNHG16 attenuated sorafenibib resistance in HCC by sponging miR-140-5p, indicating that SNHG16 might be a promising therapeutic target [115]. A study by [PERSON] et al. revealed that the lncRNA FOXD2-AS1 is a vital regulator of TMEM9. FOXD2-AS1 functioned as a sponge for miR-150-5p to modulate TMEM9 expression and contributed to sorafenib resistance [116]. Another study demonstrated that the lncRNA SNHG1 contributed to sorafenibib resistance through Akt pathway activation, and its expression is promoted by miR-21, whose nuclear translocation is induced by sorafenibib [117]. There are lncRNAs involved in various processes linked to sorafenibib resistance, such as regulation of drug efflux and metabolism [118], cellular survival and apoptosis [119], epithelial-mesenchymal transition [120], and epigenetic regulation [121]. There are other studies summarized for HCC in Table 2 whereas Table 3 depicts the studies for RCC. Table 4 includes the studies for both RCC and HCC.