ABSTRACT
Tumour metastasis is the main cause of postoperative tumour recurrence and mortality in patients with hepatocellular carcinoma (HCC), but the underlying mechanism remains unclear. Accumulating evidence has demonstrated that programmed cell death 10 (PDCD10) plays an important role in many biological processes. However, the role of PDCD10 in HCC progression is still elusive. In this study, we aimed to explore the clinical significance and molecular function of PDCD10 in HCC. PDCD10 is significantly upregulated in HCC, which also correlates with aggressive clinicopathological characteristics and predicts poor prognosis of HCC patients after liver resection. High PDCD10 expression promotes HCC cell proliferation, migration, and invasion in vitro and tumour growth, metastasis in vivo. In addition, PDCD10 could facilitate epithelial-to-mesenchymal transition (EMT) of HCC cells. In terms of the mechanism, PDCD10 directly binds to the catalytic subunit of protein phosphatase 2A (PP2Ac) and increases its enzymatic activity, leading to the interaction of YAP and dephosphorylation of the YAP protein. This interaction contributes to YAP nuclear translocation and transcriptional activation. PP2Ac is necessary for PDCD10-mediated HCC progression. Knocking down PP2Ac abolished the tumour-promoting role of PDCD10 in the migration, invasion and EMT of HCC. Moreover, a PP2Ac inhibitor (LB100) could restrict tumour growth and metastasis of HCC with high PDCD10 expression. Collectively, PDCD10 promotes EMT and the progression of HCC by interacting with PP2Ac to promote YAP activation, which provides new insight into the mechanism of cancer metastasis. PDCD10 may be a potential prognostic biomarker and therapeutic target for HCC.
Subject(s)
Apoptosis Regulatory Proteins/metabolism , Carcinoma, Hepatocellular/pathology , Epithelial-Mesenchymal Transition , Liver Neoplasms/pathology , Membrane Proteins/metabolism , Protein Phosphatase 2/metabolism , Proto-Oncogene Proteins/metabolism , YAP-Signaling Proteins/metabolism , Animals , Apoptosis Regulatory Proteins/genetics , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Nucleus/pathology , Cell Proliferation/genetics , Disease Progression , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Male , Membrane Proteins/genetics , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Models, Biological , Neoplasm Invasiveness , Prognosis , Proto-Oncogene Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Up-Regulation/genetics , Wound HealingABSTRACT
Reactive oxygen species (ROS) derived from aberrant tumor metabolism could contribute to tumor invasion and metastasis. NAD(P)HX Epimerase (NAXE), an epimerase that allows the repair of damaged forms of antioxidant NADPH, is a potential cellular ROS scavenger and its role in tumor development is still elusive. Here, we found that NAXE is significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. NAXE downregulation is associated with poor clinicopathological characteristics and is an independent risk factor for overall and disease-free survival of HCC patients after liver resection. In addition, low NAXE expression could identify worse prognosis of HCC patients before vascular invasion or in early stages of disease. In particularly, low NAXE expression in HCC is markedly associated with microvascular invasion (MVI) and its combination with MVI predicts poorer prognosis of HCC patients after liver resection. Furthermore, in vitro and in vivo experiments both showed that knockdown of NAXE expression in HCC cells promoted migration, invasion, and metastasis by inducing epithelial-mesenchymal transition (EMT), whereas NAXE overexpression causes the opposite effects. Mechanistically, low NAXE expression reduced NADPH levels and further caused ROS level increase and hypoxia-inducible factor-1α (HIF-1α) activation, thereby promoting invasion and metastasis of HCC by facilitating EMT. What is more, the tumor-promoting effect of NAXE knockdown in HCC xenograft can be abolished by giving mice N-acetyl-l-cysteine (NAC) in drinking water. Taken together, our findings uncovered a tumor suppressor role for NAXE in HCC by scavenging excessive ROS and inhibiting tumor-promoting signaling pathways, suggesting a new strategy for HCC therapy by targeting redox signaling.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver Neoplasms/metabolism , Racemases and Epimerases/metabolism , Reactive Oxygen Species/metabolism , Acetylcysteine/pharmacology , Analysis of Variance , Animals , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/secondary , Cell Movement , Disease Progression , Disease-Free Survival , Down-Regulation , Epithelial-Mesenchymal Transition , Female , Free Radical Scavengers/pharmacology , Heterografts , Humans , Liver Neoplasms/mortality , Male , Mice , Middle Aged , NADP/metabolism , Neoplasm Invasiveness , Neoplasm Proteins/metabolism , Neoplasm Transplantation , Oxidation-Reduction , Racemases and Epimerases/genetics , Risk FactorsABSTRACT
Metastasis remains the major obstacle of improving the survival of patients with hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is critical to cancer metastasis. Successful induction of EMT requires dramatic cytoskeleton rearrangement. However, the significance of microtubule (MT), one of the core components of cell cytoskeleton, in this process remains largely unknown. Here we revealed that STMN2, an important MT dynamics regulator, is barely expressed in normal live tissues but markedly up-regulated in HCCs, especially in those with early recurrence. High STMN2 expression correlates with aggressive clinicopathological features and predicts poor prognosis of HCC patients. STMN2 overexpression in HCC cells promotes EMT, invasion and metastasis in vitro and in vivo, whereas STMN2 knockdown has opposite results. Mechanistically, STMN2 modulates MTs disassembly, disrupts MT-Smad complex, and facilitates release from MT network, phosphorylation and nuclear translocation of Smad2/3 even independent of TGFß stimulation, thereby enhancing TGFß signaling. Collectively, STMN2 orchestrates MT disassembly to facilitate EMT via TGF-ß signaling, providing a novel insight into the mechanisms underlying cancer metastasis. STMN2 is a promising prognostic biomarker and potential therapeutic target for HCC.
