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    • In our study caspase and DRAM were identified as being

    2024-03-21

    In our study, caspase3 and DRAM were identified as being involved in full-length AIFM1-induced apoptosis. Caspase3 is best known for its role in the execution phase of apoptosis in both intrinsic and extrinsic apoptotic pathways [17]. The members of the caspase family are generally in inactive pro-forms, and each is cleaved to induce its activation. Pro-caspase3 becomes an active enzyme when two cleaved monomers come together to form an active dimer. When active caspase3 recognizes a specific short peptide cleavage motif (DXXD), it will cleave the proteins if this motif is accessible [18,19]. DRAM was first identified to be a p53-induced modulator of autophagy, which is critical for apoptosis [15]. Recently, many studies have demonstrated that overexpression of DRAM can induce apoptosis in many different tumor cells [20]. Moreover, our previous studies demonstrated that the translocation of DRAM to mitochondria induces mitochondria autophagy (mitophagy), and this DRAM-induced mitophagy can induce apoptosis [21,22], suggesting that DRAM-mediated mitophagy might also be involved in apoptosis induced by full-length AIFM1. Taken together, our study uncovers a new role of full-length AIFM1 in inducing apoptosis and CHC arrest. We believe that the use of rAd-AIFM1 encoding full-length AIFM1 might be a potential HCC gene therapy, and its HCC inhibitory effect will be further detected in vivo in the future.
    Conflicts of interest
    Acknowledgements This work was supported by National Natural Science Foundation of China (NSFC 81402556, 81773168) and the Foundation of Beijing Institute of Hepatology (BJIH-01715).
    Introduction Regeneration is a dynamic biological process that is aimed at restoring tissue integrity and maintaining homeostasis following injury. Injury is caused by wounding due to trauma, or pathologies like infection and cancer [1]. Regeneration requires a coordinated series of various intracellular, extracellular and intercellular signaling events. Each of these events needs to be tightly regulated to achieve homeostasis and to prevent excessive healing responses. Defects in wound repair can cause non-healing ulcers, or excessive invasive proliferation leading to cancer. Indeed, a classical theory by Harold Dvorak postulates that “tumors are wounds that do not heal” [2]. This theory was proposed based on observations that both wounds and tumors share common cellular properties. For example, the composition of the tumor stroma resembled the granulation tissue observed during wound healing. The major difference between wounds and tumors is that in contrast to wound healing, the process is not self-limiting in tumors, and continuous activation of the involved signaling events causes hyperproliferation, invasion, and finally metastasis. The ability to repair tissue after an injury is a fundamental property of multicellular organisms, though the regenerative responses are quite diverse, and depend on the species, organ and the developmental stage [3]. Most species have the capacity to regenerate missing body parts or organs, either completely or with formation of a scar, while a few species like primitive sponges, Hydra, and planarians can regenerate the entire organism from parts of their body [4]. Some animals are capable of regenerating their tissue throughout life, while others show a developmental stage-specific restriction of the ability to regenerate. While most mature mammals maintain the ability to regenerate a few select organs such as the liver, they have largely lost the capacity to regenerate lost tissue. Regeneration follows a succession of events including an immediate wound healing response, followed by formation of a regenerative structure called blastema, leading to proliferation and differentiation, and finally complete restoration of the lost tissue or appendage. Wound healing, the first stage of regeneration, is initiated immediately after an injury, and involves recruitment of immune cells like neutrophils and macrophages, inflammation, and formation of a clot. Actomyosin cables are extended across the wound edge, the extracellular matrix is remodeled, and the wound is closed. Formation of a blastema is a critical step in regeneration, and usually occurs prior to complete wound closure [5]. The blastema is the site for regenerative proliferation, and consists of both differentiated cells and stem cells. The cells in the blastema give rise to new cells by multiple different mechanisms including stem cell proliferation, compensatory proliferation, cell cycle re-entry of differentiated cells, dedifferentiation, or transdifferentiation [3]. Finally there is remodeling of the newly formed cells to establish epithelial integrity, which restores a fully patterned organ or limb.