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  • HCC metastasis is a multistep multifactorial

    2021-09-09

    HCC metastasis is a multistep, multifactorial process, including adhesion of tumor glycerol phosphate to the extracellular matrix (ECM), remodeling and degradation of ECM, invasion through local tissue, intravasation into blood or lymph vessels, and forming new tumors at distant sites [6,7]. Loss of adhesion or adhesion-mediated signaling results in programmed cell death, referred to as anoikis. Anoikis has been suggested to act as a physiological barrier to metastasis and is an early step in preventing cancer metastasis [8,9]. However, anoikis resistance endues malignant tumor cells with anchorage-independent growth, which has a crucial role in tumor metastasis. The cancer cells exploit many mechanisms to confer anoikis resistance, including deregulation of integrin, aberrant constitutive activation of serval anti-apoptotic or prosurvival pathways, undergoing epithelial–mesenchymal transition (EMT), and altered metabolism [10,11]. However, the mechanisms responsible for anoikis resistance of HCC are still not fully understood. Zinc finger protein 32 (ZNF32) belongs to the Krüppel-like family of transcription factors that are critical for normal biologic processes as well as cancer development [12,13]. Our previous study demonstrates that knockout of ZNF32 promotes the regeneration of the lateral line system in zebrafish [14]. ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription [15]. Furthermore, ZNF32 dysregulation is associated with multidrug resistance in lung adenocarcinoma [16]. However, the role of ZNF32 in HCC progression remains unknown. In the present study, we provided the first evidence that ZNF32 was up-regulated in HCC cells upon detachment. ZNF32 overexpression significantly promoted the anchorage-independent growth capability of HCC cells. Mechanistically, we demonstrated that ZNF32 maintained mitochondrial function through inhibition of excess ROS accumulation and promoted the phosphorylation of Src/FAK signaling. Taken together, our study indicated that ZNF32 induced the anoikis resistance of HCC cells by maintaining redox homeostasis and activating Src/FAK signaling, implicating ZNF32 as a potential therapeutic target of advanced HCC.
    Materials and methods
    Results
    Discussion Anoikis, defined as detachment-induced apoptosis, exerts as a barrier to cancer metastasis. Resistance to anoikis is known as a critical step in metastasis, as it compromises tumor cells to survive in the systemic circulation and facilitates their metastasis to distant organs [24,25]. However, the molecular mechanism of anoikis resistance in HCC remains not fully understood. In the present study, we found that ZNF32 expression was significantly upregulated in HCC cells following detachment. Overexpression of ZNF32 promoted the resistance to anoikis, whereas ZNF32 suppression resulted in reduced anchorage-independent growth in HCC cells. Our data revealed a crucial role for ZNF32 in regulating HCC malignant progression. Recent studies have demonstrated that ECM-detachment induces robustly increased basal ROS levels that can cause damage to cellular components and ultimately lead to cell death [26,27]. Strikingly, cancer cells seemed to benefit from the elimination of ECM-detachment mediated ROS production as overexpression of the ErbB2 oncogene led to luminal filling and diminished ROS levels [28]. Here, we reported that overexpression of ZNF32 significantly repressed ROS levels and enhanced antioxidant-scavenging capacity as indicated by accumulation of two intracellular antioxidants GSH and NAPDH to promote survival of suspended HCC cells. Moreover, the defect of anchorage-independent growth caused by ZNF32 deficiency was restored by antioxidants NAC or GSH treatment. Consistent with our study, a recent study reported that antioxidant enhanced anchorage-independent colony formation of breast cancer cells [29]. Furthermore, additional studies have revealed that upregulated pyruvate dehydrogenase kinase 4 attenuated the production of ROS through stalling the flux of glycolytic carbon into mitochondrial oxidation to enable cell survival during ECM-detachment [30]. Based on elevated ROS levels are essential to promote tumor cell survival and malignant progression [31,32], we hypothesize that cancer cells need to both inhibit anoikis and appropriately regulate ROS levels to survive during the metastatic cascade.