AMPK is a central regulator of cell growth

AMPK is a central regulator of cell growth, migration, metabolism, autophagy, and cell polarity [20], [21], [22], [23]. It is highly conserved in eukaryotes and functions as the primary sensor of intracellular adenosine nucleotides [24]. When intracellular ATP levels decrease, AMPK is activated to generate more ATP by promoting catabolic pathways and inhibiting anabolic pathways [25], [26]. Previous studies also demonstrate that AMPK functions as a tumor suppressor in various types of cancers. Indeed, loss of AMPKα1 enhances the Warburg effect in cancer cells and accelerates Myc-driven lymphomagenesis in vivo[27]. Decreased AMPK expression has also been observed in many breast cancer cell lines. Moreover, AMPK activation suppresses aromatase, which subsequently inhibits estrogen formation and prevents breast cancer growth [28]. In prostate cancer cells, inhibition of AMPK alters gene expression and accelerates cell proliferation and migration [29], while AMPK activation by MT 63–78, a direct AMPK activator, inhibits cell growth in vitro and tumor growth in vivo[30]. In the present study, we found lower AMPK expression in HCC clinical samples, which supports observations in other types of cancer. TRIM24 was also shown to inhibit AMPK expression in vitro and in vivo, while AMPK knockdown in an established sh-TRIM24-Huh7 cell line increased cell proliferation and clone formation in vitro as well as tumor progression in vivo, demonstrating that TRIM24 promotes HCC progression through AMPK-related pathways. In the current literature, TRIM24 function in HCC progression is controversial. It functions as a liver-specific tumor suppressor in mice [31], [32] and forms regulatory complexes with other TRIM family members to suppress mouse HCC [33], [34]. However, Liu et al. [19] observed elevated TRIM24 expression in human HCC tissues that appears to be positively correlated with alpha-fetoprotein (AFP) concentration, poor differentiation, intrahepatic metastasis, tumor recurrence, and shorter tumor-free survival time. Downregulation of TRIM24 in the human HCC cell line HePG2 also promotes apoptosis and epithelial-to-mesenchymal transition (EMT). In addition, TRIM24 overexpression has been reported in various human cancers, including gastric cancer, latanoprost cancer, non-small cell lung cancer, head and neck carcinoma, human HCC, and breast cancer [19], [35], [36], [37], [38], [39], [40], [41]. When considering the opposing research surrounding TRIM24 function in HCC progression, we believe that there may be species-specific factors that define TRIM24 as an oncogene or tumor suppressor in HCC, which need to be further evaluated in both human and mouse HCC. In summary, our study provides evidence that TRIM24 promotes human HCC cell proliferation and migration in vitro and tumor progression in vivo. This function for TRIM24 in HCC appears to be largely mediated by AMPK signaling. Clinically, elevated levels of TRIM24 in human HCC samples are associated with higher tumor grade and decreased AMPK expression. Taken together, our data indicate an important role for TRIM24 in human HCC progression and provide insight into new therapeutic targets for human HCC treatment.
Conflict of interest
Introduction In 2016, the Third International Consensus Definitions Task Force (Sepsis-3) defined sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al., 2016). Although the exact mechanism remains unclear, it is widely postulated that release of immune chemicals (e.g., cytokines, chemokines, and damage-associated molecular patterns [DAMPs]) by innate immune cells (e.g., macrophages and monocytes) plays a major role in mediating septic death (Wiersinga et al., 2014, Srivastava and Mannam, 2015). In particular, extracellular high mobility group box 1 (HMGB1), the prototypical DAMP, is a late mediator of experimental sepsis with a wider therapeutic window (Wang et al., 1999, Wang et al., 2001). HMGB1 is not only secreted in inflammatory conditions, but also released in cell death (Scaffidi et al., 2002, Tsung et al., 2005). Once released, HMGB1 amplifies the inflammatory responses to tissue injury and infection (Kang et al., 2014). For example, HMGB1 can bind to multiple cell surface receptors such as RAGE and TLR4 to produce proinflammatory cytokines, chemokines, and adhesion molecules in various immune cells (Kang et al., 2014). Moreover, extracellular HMGB1 is capable of binding to various immune stimuli such as lipopolysaccharide (LPS), DNA, and IgG to produce synergistic effects on the inflammatory response (Kang et al., 2014). Thus, HMGB1 is a therapeutic target for various lethal inflammatory diseases, including sepsis (Wang et al., 2014).