Overexpression of ZFP69B promotes hepatocellular carcinoma growth by upregulating the expression of TLX1 and TRAPPC9.

T-cell leukemia homeobox protein 1 (TLX1) has been revealed as a hub transcription factor in leukemia, while its function in hepatocellular carcinoma (HCC) has not been well described. Here, we investigated the regulation and function of TLX1 in HCC. TLX1 and its possible upstream and downstream molecules in HCC were identified using bioinformatics tools, which were then verified by RT-qPCR assay. CCK-8, wound healing, and Transwell invasion assays were performed to detect the effects of TLX1 knockdown on HCC cells. The interactions between TLX1 and trafficking protein particle complex subunit 9 (TRAPPC9) or Zinc finger protein 69 homolog B (ZFP69B) were further probed by ChIP and luciferase reporter assays. Rescue experiments were finally conducted in vitro and in vivo. TLX1 was highly expressed in HCC cells, and the knockdown of TLX1 led to reduced malignant biological behavior of HCC cells. TLX1 bound to the promoter region of TRAPPC9, thereby promoting TRAPPC9 expression. Overexpression of TRAPPC9 attenuated the effect of TLX1 reduction on suppressing malignant behavior of HCC cells. ZFP69B was also highly expressed in HCC cells and bound to the promoter region of TLX1 to induce TLX1 expression. Knockdown of ZFP69B inhibited the viability and mobility of HCC cells in vitro and tumor growth in vivo, and overexpression of TLX1 rescued this inhibition. These findings suggest that ZFP69B promotes the proliferation of HCC cells by directly upregulating the expression of TLX1 and the ensuing TRAPPC9.

被引量：- 发表：1970

Long non-coding RNA NEAT1 induced by BHLHE40 activates Wnt/β-catenin signaling and potentiates colorectal cancer progression.

被引量：- 发表：1970

The interplay of transition metals in ferroptosis and pyroptosis.

Cell death is one of the most important mechanisms of maintaining homeostasis in our body. Ferroptosis and pyroptosis are forms of necrosis-like cell death. These cell death modalities play key roles in the pathophysiology of cancer, cardiovascular, neurological diseases, and other pathologies. Transition metals are abundant group of elements in all living organisms. This paper presents a summary of ferroptosis and pyroptosis pathways and their connection to significant transition metals, namely zinc (Zn), copper (Cu), molybdenum (Mo), lead (Pb), cobalt (Co), iron (Fe), cadmium (Cd), nickel (Ni), mercury (Hg), uranium (U), platinum (Pt), and one crucial element, selenium (Se). Authors aim to summarize the up-to-date knowledge of this topic.In this review, there are categorized and highlighted the most common patterns in the alterations of ferroptosis and pyroptosis by transition metals. Special attention is given to zinc since collected data support its dual nature of action in both ferroptosis and pyroptosis. All findings are presented together with a brief description of major biochemical pathways involving mentioned metals and are visualized in attached comprehensive figures.This work concludes that the majority of disruptions in the studied metals' homeostasis impacts cell fate, influencing both death and survival of cells in the complex system of altered pathways. Therefore, this summary opens up the space for further research.

被引量：1 发表：1970

Depletion of NUAK2 blocks the stemness and angiogenesis and facilitates senescence of lung adenocarcinoma cells via enhancing ferroptosis.

NUAK family kinase 2 (NUAK2) has been identified as an important mediator for tumor progression in multiple malignancies. Nevertheless, its role in lung adenocarcinoma (LUAD) remains unclear. Bioinformatic analysis was performed to assess the expression and prognosis of NUAK2 in patients with LUAD. The NUAK2 expression was measured in multiple LUAD cell lines, and the loss-of-function experiment was conducted. Cell proliferation ability was assessed using CCK-8 and colony formation assays. Spheroid formation, alkaline phosphatase (AP) staining, tube formation and SA-β-gal staining assays were performed to examine stemness, angiogenesis and senescence. Lipid peroxidase was assessed by TBARS production and lipid ROS. Western blot was used to detect critical proteins. In addition, A549 cells were treated with ferroptosis inhibitor ferrostatin-1 (Fer-1) for a rescue assay. Finally, A549 cells were subcutaneously injected into the right flank of mice to establish LUAD-bearing mouse model, and the tumor weight and size were detected. NUAK2 was upregulated in patients with LUAD and LUAD cell lines. NUAK2 depletion inhibited cell viability, colonies, tumor spheres and decreased Oct4 and Nanog expression, confirming NUAK2 depletion inhibited proliferation and stemness of A549 cells. Meanwhile, NUAK2 depletion blocked angiogenesis via reducing formed tubes and VEGFR1/2 expression, and promoted senescence of A549 cells by elevating SA-β-gal-positive cells and p16, p21 and p53 expression. Moreover, NUAK2 depletion elevated lipid ROS, TBARS production and Fe2+ level, demonstrating that NUAK2 depletion could trigger ferroptosis in A549 cells. Furthermore, the rescue experiments revealed that the impacts of NUAK2 depletion on malignant behaviors in A549 cells were partly weakened by additional Fer-1 treatment. Finally, in vivo experiments demonstrated that NUAK2 knockdown greatly inhibited tumor growth in LUAD-bearing mice. In summary, NUAK2 depletion impeded oncogenic phenotypes of A549 cells partly via triggering ferroptosis, suggesting NUAK2 as a novel target for treating LUAD.

被引量：1 发表：1970

NPRL2 is required for proliferation of oncogenic Ras-transformed bronchial epithelial cells.

Nitrogen permease regulator-like 2 (NPRL2/TUSC4) is known to exert both tumor-suppressing and oncogenic effects in different types of cancers, suggesting that its actions are context dependent. Here, we delineated the molecular and functional effects of NPRL2 in malignantly transformed bronchial epithelial cells. To do so, we depleted NPRL2 in oncogenic HRas-transduced and malignantly transformed human bronchial epithelial (BEAS2B), Ras-AI-T2 cells. Intriguingly, depletion of NPRL2 in these cells induced activation of mTORC1 downstream signaling, inhibited autophagy, and impaired Ras-AI-T2 cell proliferation both in vitro and in vivo. These results suggest that NPRL2 is required for oncogenic HRas-induced cell transformation. Depletion of NPRL2 increased levels of the DNA damage marker γH2AX, the cell cycle inhibitors p21 and p27, and the apoptosis marker cleaved-PARP. These NPRL2-depleted cells first accumulated at G1 and G2, and later exhibited signs of mitotic catastrophe, which implied that NPRL2 depletion may be detrimental to oncogenic HRas-transformed cells. Additionally, NPRL2 depletion reduced heat shock factor 1/heat shock element- and NRF2/antioxidant response element-directed luciferase reporter activities in Ras-AI-T2 cells, indicating that NPRL2 depletion led to the suppression of two key cytoprotective processes in oncogenic HRas-transformed cells. Overall, our data suggest that oncogenic HRas-transduced and malignantly transformed cells may depend on NPRL2 for survival and proliferation, and depletion of NPRL2 also induces a stressed state in these cells.

被引量：- 发表：1970