BCL11B suppresses tumor progression and stem cell traits in hepatocellular carcinoma by restoring p53 signaling activity

Abstract

Accumulating evidence indicates that hepatocellular carcinoma (HCC) tumorigenesis, recurrence, metastasis, and therapeutic resistance are strongly associated with liver cancer stem cells (CSCs), a rare subpopulation of highly tumorigenic cells with self-renewal capacity and differentiation potential. Previous studies identified B cell leukemia/lymphoma-11b (BCL11B) as a novel tumor suppressor with impressive capacity to restrain CSC traits. However, the implications of BCL11B in HCC remain unclear. In this study, we found that low BCL11B expression was an independent indicator for shorter overall survival (OS) and time to recurrence (TTR) for HCC patients with surgical resection. In vitro and in vivo experiments confirmed BCL11B as a tumor suppressor in HCC with inhibitory effects on proliferation, cell cycle progression, apoptosis, and mobility. Furthermore, BCL11B could suppress CSC traits, as evidenced by dramatically decreased tumor spheroid formation, self-renewal potential and drug resistance. A Cignal Finder Array and dual-luciferase activity reporter assays revealed that BCL11B could activate the transcription of P73 via an E2F1-dependent manner. Thus, we concluded that BCL11B is a strong suppressor of retaining CSC traits in HCC. Ectopic expression of BCL11B might be a promising strategy for anti-HCC treatment with the potential to cure HBV-related HCC regardless of P53 mutation status.

Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy

“…It highlighted the crucial function of BCL11B, which is increased after ACSL4 overexpression, in lipid metabolism. Yang et al reported that BCL11B expression greatly sensitizes HepG2 and Huh7 hepatocarcinoma cell lines towards doxorubicin [50] . Besides, the signaling transduction factor GDF15, which is a secreted cytokine of TGF-β superfamily, is decreased after ACSL4 overexpression.…”

Non‐coding RNA‐associated competitive endogenous RNA regulatory networks: Novel diagnostic and therapeutic opportunities for hepatocellular carcinoma

“…Orthotopic liver transplantation (OLT) and surgical resection are known as the most effective approaches for HCC treatment. However, a high rate of metastasis/recurrence (~50%–70%) has been observed within five years post‐operation 7 . Although sorafenib and regorafenib are used as the first‐ and second‐line systemic chemotherapy for HCC, concerns about drug resistance, which leads to a high mortality rate, are rising.…”

“…However, a high rate of metastasis/recurrence (~50%–70%) has been observed within five years post‐operation. 7 Although sorafenib and regorafenib are used as the first‐ and second‐line systemic chemotherapy for HCC, concerns about drug resistance, which leads to a high mortality rate, are rising. Over the recent decades, a large body of evidence has been obtained about the role played by genes crucial for cellular processes, such as cell cycle control, cell growth, apoptosis and migration in HCC development.…”

Downregulation of THRSP Promotes Hepatocellular Carcinoma Progression by Triggering ZEB1 Transcription in an ERK-dependent Manner

“…Western blotting was performed following previous studies [14]. The utilized antibodies included anti-THRSP (1:500, sc-516102; Santa Cruz), anti-phospho-ERK (Tyr202/Tyr204) (1:1000, 4377S; CST), anti-ERK (1:1000, 4695S; CST), anti-Slug (1:1000, 9585S; CST), anti-Snail (1:1000, 3879S; CST), anti-Twist (1:1000, 46702S; CST), anti-ZEB1 (1:1000, 70512S; CST), anti-ZEB2 (1:1000, 3396S; CST).…”