# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
### Primary Resistance
#### 1.2.3 Vascular Endothelial Growth Factor A (VEGFA)  
VEGF is a critical cellular target of sorafenibib. It was initially isolated from tumor cells and is involved in glioma cell proliferation, angiogenesis, and metastasis [57]. VEGFA exerts its effects primarily by activating the AKT and AMPK signaling pathways, which play crucial roles in cell survival, proliferation, and metabolism. VEGF stimulates paracrine secretion of hepatocyte growth factor by stromal cells, which promotes tumor progression [1; 58]. It is a potent pro-angiogenic factor that promotes the formation of new blood vessels, a process crucial for tumor growth and metastasis. In HCC, VEGFA is often overexpressed, leading to enhanced angiogenesis and tumor progression. VEGFA binds to its receptor VEGFR2, initiating a series of downstream signaling events that activate various cellular pathways involved in proliferation, survival, and resistance to apoptosis. Upon VEGFA binding to VEGFR2, the receptor undergoes autophosphorylation, which activates phosphoinositide 3-kinase (PI3K). Activated PI3K then converts PIP2 to PIP3, which recruits AKT to the plasma membrane, which is phosphorylated and activated. Activated AKT promotes cell survival by inhibiting pro-apoptotic factors such as BAD and by upregulating cell proliferation pathways, enhancing the survival capacity of tumor cells under sorafenibib-induced stress [51]. AMPK activation enhances glucose uptake and fatty acid oxidation, providing the energy necessary for cell survival under therapeutic stress. This metabolic adaptation is crucial for the primary resistance of HCC cells to sorafenibib. The association between lncRNA and VEGFA has also been studied. lncRNA (UBE2 CP3) enhances VEGFAsecretion and promotes angiogenesis in HCC cells by activating ERK1/2/HIF-1\(\alpha\)/VEGFAsignaling in hepatocellular carcinoma [59; 60]. C-JunN-terminal kinase; JNK (Mitogen-Activated Protein Kinase; MAPKfamily) JNK (c-Jun N-terminal kinase) is a member of the MAPK (mitogen-activated protein kinase) family that regulates a range of biological processes implicated in tumorigenesis and neurodegenerative disorders. It is also known as the AP-1 transcription factor subunit. It is located at 1p32-p31; the deletion and translocation of this chromosomal have been associated with the development of malignant tumors. In a study performed by [PERSON] et al., the authors demonstrated that the overexpression of c-Jun contributes to sorafenib resistance in HCC [61; 62] and the modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Preliminary clinical evidence by [PERSON] et al. showed that the prediction of c-Jun activation demonstrates a poor response to sorafenib in HCC [60]. This in vitro study showed that sorafenib treatment could activate the expression of c-Jun, while its inhibition significantly enhanced sorafenib-induced apoptosis in HCC cells. In another study by [PERSON] et al., activation of JNK and a high expression level of CD133 predicted a poor response to sorafenib in HCC. JNK activity was significantly correlated with CD133 expression level, and the high expression level of CD133 was linked to a poor reaction to Sorafenib [63].  
LncRNAs contribute to various biological processes by associating with RNA-binding proteins (RBPs) [57]. Understanding the multiple functions of VEGFA and its regulation by lncRNA INC0116 has been shown in glioma tumorigenesis. The novel lncRNA INC01116, when knocked down, suppresses growth, invasion, metastasis, tumorigenesis, and angiogenesis in glioma both in vitro and in vivo by regulating VEGFA expression [57]. It will be interesting to study the role of lncRNA INC01116 in sorafenib resistance, which has not been reported yet.