# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
### Secondary Resistance
#### 1.3.5 Hypoxia  
The tumor microenvironment plays a vital role in the development of tumors. Anti-angiogenic drugs can cause blood vessel contraction in the tumor and, in turn, reduce the blood flow. Reduction in blood flow results in oxygen deprivation within the tumor. Based on recent studies, hypoxia in tumors is associated with chemotherapy failure, the selection of more invasive and resistant clones, and/or poor prognosis. Hypoxia plays a vital role in the development as well as the progression of tumors. It has also been implicated in developing drug resistance and activating tumor metastasis. Continuous treatment with sorafenib results in the inhibition of the tumor's anti-angiogenic activity, which can subsequently induce hypoxia in the tumor. This further promotes the selection of resistant cell clones to adapt to hypoxic conditions, thereby limiting the efficacy of sorafenib.  
A study by [PERSON] et al. [PERSON] et al. (2018); [PERSON] et al. (2019) demonstrated that hypoxia induced by continued sorafenibib treatment resulted in sorafenibb resistance via HIF-1\(\alpha\)/NF-kB activation in HCC EF24, a molecule with structural similarities to curcumin, which could synergistically augment sorafenibib's antitumor effects and help overcome sorafenibb resistance by HIF-1\(\alpha\) inhibition [PERSON] et al. (2019). Another study by [PERSON] et al. showed that HSP90\(\alpha\) plays a key role in sorafenibb resistance under hypoxia by blocking necroptosis. The author proved that HSP90\(\alpha\) binds with the RIPK1/RIPK3/MLKL complex to induce autophagy, which would be the leading cause of sorafenibb resistance. 17-allylamino-17-demethoxyygeldanamycin (17-AAG), a specific inhibitor of HSP90\(\alpha\), was able to overcome sorafenibb resistance in HCC [PERSON] et al. (2018). demonstrated that sorafenibb upregulates HIF-2\(\alpha\) by switching the hypoxia response from HIF-1\(\alpha\) to HIF-2\(\alpha\)-dependent pathways, resulting in the activation of the TGF-\(\alpha\)/EGFR pathway, which contributes to the resistance of HCC cells to sorafenibb [PERSON] et al. (2019). These studies proved a relationship between high HIF expression and sorafenibb resistance, demonstrating that hypoxia impacts sorafenibb treatment and suggested hypoxia induction as a promising approach to overcome resistance.  
Hypoxia-mediated lncRNAs have been demonstrated to induce tumor metastasis. Recent studies have increasingly focused on the relationship between hypoxia, lncRNAs, and several cancers [PERSON] et al. (2019). For example, hypoxia-induced TUFT1 is proposed to facilitate HCC growth and metastasis by activating the Ca(2+)/PI3K/AKT pathway [PERSON] et al. (2019), and hypoxia-induced HMGB1 mediates HCC and RCCtumor growth via the Toll-like receptor [PERSON] et al. (2019). Current data show that hypoxia-induced HMGB1 boosts HCC tumor invasiveness and metastasis by modulating macrophage-derived IL-6. The liver-specific putative lncRNA, AC115619, is also expressed at low levels in HCC. Both AC115619-22 aa and AC115619 play crucial roles in tumor progression and serve as prognostic indicators in HCC and RCC [PERSON] et al. (2019).