E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation

Abstract

The mammalian target of rapamycin (mTOR) pathway is frequently deregulated and has critical roles in cancer progression. mTOR inhibitor has been widely used in several kinds of cancers and is strongly recommended in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). However, the poor response to mTOR inhibitors due to resistance remains a challenge. Hypoxia‐associated resistance limits the therapeutic efficacy of targeted drugs. The present study established models of HCC clinical samples and cell lines resistance to mTOR inhibitor sirolimus and screened out E2F7 as a candidate gene induced by hypoxia and promoting sirolimus resistance. E2F7 suppressed mTOR complex 1 via directly binding to the promoter of the TSC1 gene and stabilizes hypoxia‐inducible factor‐1α activating its downstream genes, which are responsible for E2F7‐dependent mTOR inhibitor resistance. Clinically, low E2F7 expression could be an effective biomarker for recommending patients with HCC for anti‐mTOR–based therapies after LT. Targeting E2F7 synergistically inhibited HCC growth with sirolimus in vivo. E2F7 is a promising target to reverse mTOR inhibition resistance. Collectively, our study points to a role for E2F7 in promoting mTOR inhibitor resistance in HCC and emphasizes its potential clinical significance in patients with HCC after LT.

USP22 promotes tumorigenesis and progression by a FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma

“…In fact, our previous studies exhibited similar results. We found that LT recipients with HCC beyond Milan Criteria could bene t from SRL-based immunosuppression (39), and low TSC1/2 expression subgroup (higher tumor activity) bene ted the most (20,40). Therefore, it was conceivable that USP22 expression level could potentially help stratify recipients, who might particularly bene t from sirolimus.…”

Ubiquitin‐specific protease 22 promotes tumorigenesis and progression by an FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma

“…Our previous study yielded similar results. We found that LT recipients with HCC exceeding the Milan Criteria could benefit from sirolimus‐based immunosuppression, 36,37 and the low TSC1/2 expression subgroup (higher tumor activity) benefited the most 38,39 . Therefore, USP22 expression levels could help stratify recipients, who might benefit from sirolimus.…”

“…We found that LT recipients with HCC exceeding the Milan Criteria could benefit from sirolimus-based immunosuppression, 36,37 and the low TSC1/2 expression subgroup (higher tumor activity) benefited the most. 38,39 Therefore, USP22 expression levels could help stratify recipients, who might benefit from sirolimus. Here, we presented that sirolimus-based immunosuppression could improve OS in LT recipients beyond the Milan Criteria with high USP22 expression, which was in accordance with in vitro and in vivo experiments.…”

Identification of hypoxia‐related gene signatures based on multi‐omics analysis in lung adenocarcinoma

“…For example, in hepatocellular carcinoma cell lines, hypoxia could induce E2F7 expression and promote sirolimus resistance. And E2F7 could activate downstream genes by stabilizing HIF‐1α 73 . In breast cancer cell lines, hypoxia can modulate EGFR expression and downstream signalling in a DNA methylation‐specific and HIF‐dependent manner, altering the response to anti‐ EGFR therapy 74 .…”

“…And E2F7 could activate downstream genes by stabilizing HIF‐1α. 73 In breast cancer cell lines, hypoxia can modulate EGFR expression and downstream signalling in a DNA methylation‐specific and HIF‐dependent manner, altering the response to anti‐ EGFR therapy. 74 In the liver metastatic tissue derived from patients of colorectal cancer, SCGB2A1 was identified as a novel hypoxia‐inducible gene and prognostic marker associated with chemoresistance and radioresistance.…”