CircRNA-mTOR Promotes Hepatocellular Carcinoma Progression and Lenvatinib Resistance via PSIP1/c-Myc Axis Nuclear Translocation and Partially through Increasing EGFR Expression

Abstract

Background Hepatocellular Carcinoma (HCC) is one of the major malignant tumors threatening human health. Lenvatinib resistance seriously restricts the efficacy of HCC, but the specific mechanism is not clear. Circular RNA (circRNA) plays an important role in the regulation of tumor drug resistance. Methods Key circRNA was screened by bioinformatics methods, and further identified by relevant validation experiments and HCC tissue samples. And, circRNA was evaluated as a diagnostic and prognostic marker for HCC progression at the clinical level. After then, through in vivo and in vitro experiments, the specific mechanism of the circRNA on the progression of HCC and lenvatinib resistance was explored at the molecular level. Results circRNA_0009792 (circRNA-mTOR) was highly expressed in HCC and is closely related to the prognosis of patients, which has good diagnostic value and clinical significance. In vivo and in vitro experiments showed that circRNA-mTOR could promote the progression of hepatocellular carcinoma and promote lenvatinib resistance by improving the stemness of HCC cells. Mechanismly, circRNA-mTOR could affect RNA-binding protein (PSIP1) nuclear translocation by specifically binding to it, and then which enhanced the stemness of HCC cells through PSIP1/c-Myc axis, hence promoting the progression of HCC and lenvatinib resistance. And furthermore, circRNA-mTOR at least partially induce lenvatinib resistance by increasing the expression of EGFR in HCC. Conclusions In conclusion, this study suggests that circRNA-mTOR can affect PSIP1/c-myc axis nuclear translocation, to make progress of HCC and the maintenance of steness of liver cancer cell to aggravate lenvatinib resistance, And partially increased EGFR over-expression to making chemo-resistance worse. CircRNA-mTOR has the potential to be a biomarker for the diagnosis and prognosis of HCC. This study provides a certain experimental basis for the targeted drug therapy of HCC, and puts forward new ideas, new insights and new methods in understanding the occurrence and development of HCC, and it is of great significance to seek new markers and targets for the diagnosis and treatment of HCC and reduce drug resistance.

A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma

“…Several intracellular consequences result from this, including reduced nucleotide availability, oxidative stress, DNA damage, and impaired antioxidant defense, which increases sorafenib sensitivity. It becomes obvious why PHGDH knockout would increase HCC cells’ susceptibility to sorafenib-induced apoptosis by linking its role in cell survival and proliferation with the stress and DNA damage response [ 111 – 113 ].…”