LncRNA HABON promoted liver cancer cells survival under hypoxia by inhibiting mPTP opening

Abstract

Hypoxia is an important feature of the tumor microenvironment (TME). While targeting hypoxic TME is emerging as a potential strategy for treating solid tumors including liver cancer. Recent studies have shown that hypoxia can regulate tumor adaptation to hypoxic TME through long non-coding RNA (lncRNA). In the previous study, we identify a novel hypoxia-activated lncRNA and termed it as HABON. Here, we demonstrated that knockdown of HABON caused necroptosis of tumor tissue and inhibited the subcutaneous tumor growth of SMMC-7721 cells in nude mice. Moreover, knockdown of HABON increased RIPK1 and MLKL expression as well as their phosphorylation level in SMMC-7721 and Huh7 liver cancer cells. Meanwhile, Necrostatin-1 and GSK872 could restore cell death of liver cancer cells caused by knockdown of HABON under hypoxia. The above results suggested that HABON could inhibit hypoxia-induced necroptosis of liver cancer cells. Mechanically, knockdown of HABON in liver cancer cells aggravated mitochondrial dysfunction caused by hypoxia. Furthermore, the RNA pull-down combined with mass spectrometry analysis identified HABON can interact with mitochondria-related protein VDAC1 and the RNA immunoprecipitation (RIP) analysis proved the interaction. In addition, we proved that VDAC1 mediated the mitochondrial permeability transition pore (mPTP) opening, mitochondrial dysfunction, as well as necroptosis caused by knockdown of HABON. Overall, our work demonstrates HABON can reduce hypoxia-induced necroptosis of liver cancer cells and suggests that inhibition of HABON in the hypoxic TME is a potential therapeutic strategy for treating liver cancer.

Ferroptosis-related lncRNA model based on CFAP58-DT for predicting prognosis and immunocytes infiltration in endometrial cancer

“…The lncRNA KRT19P3 prevents breast cancer progression via immune pathways, thereby reducing programmed cell death 1 ligand 1 (PD-L1) expression and enhancing cluster of differentiation (CD) 8 + T cell expression (36). Moreover, as a crucial feature of the TME, hypoxia activates the lncRNA HABON and prolongs the survival of liver cancer tissues through the inhibition of necroptosis (37). Besides, there was a report saying that the signature composed of 11 ferroptosis-related lncRNAs accurately predicted the prognosis of ovarian cancer patients (38).…”

A New Necroptosis-Related lncRNA Signature Predicts the Prognosis of Kidney Renal Clear Cell Carcinoma Patients

“…LncRNA-107053293 regulated necroptosis by acting as a competing endogenous RNA of miR-148a-3p.FAF1 (Wang W et al 2020). LncRNA HABON can reduce hypoxia-induced necroptosis of liver cancer cells and suggests that inhibition of HABON in the hypoxic TME is a potential therapeutic strategy for treating liver cancer (Wo L et al 2022). However, its speci c role and impact on the prognosis of KIRC patients remain unclear.…”

COVID‐19 metabolism: Mechanisms and therapeutic targets

“… 184 The opening of mPTP increases mitochondria permeability and leads to mitochondrial swelling. 185 Viral proteins may hamper mitochondrial function through binding to mPTP and destructing mitochondrial inner membrane integrity. Depolarization of mitochondria could further impair mitophagy and cause apoptosis.…”

“…Mitochondrial permeability transition pore (mPTP) is a protein complex formed in the inner membrane under specific pathological conditions 184 . The opening of mPTP increases mitochondria permeability and leads to mitochondrial swelling 185 . Viral proteins may hamper mitochondrial function through binding to mPTP and destructing mitochondrial inner membrane integrity.…”