RESUMO
The RNA-binding protein PNO1 plays an essential role in ribosome biogenesis. Recent studies have shown that it is involved in tumorigenesis; however, its role in hepatocellular carcinoma (HCC) is not well understood. The purpose of this study was to examine whether PNO1 can be used as a biomarker of HCC and also examine the therapeutic potential of PNO1 knockout for the treatment of HCC. PNO1 expression was upregulated in HCC and associated with poor prognosis. PNO1 expression was positively associated with tumour stage, lymph node metastasis and poor survival. PNO1 expression was significantly higher in HCC compared to that in fibrolamellar carcinoma or normal tissues. Furthermore, HCC tissues with mutant Tp53 expressed higher PNO1 than those with wild-type Tp53. PNO1 knockout suppressed cell viability, colony formation and EMT of HCC cells. Since activation of Notch signalling pathway promotes HCC, we measured the effects of PNO1 knockout on the components of Notch pathway and its targets. PNO1 knockout suppressed Notch signalling by modulating the expression of Notch ligands and their receptors, and downstream targets. PNO1 knockout also inhibited genes involved in surface adhesion, cell cycle, inflammation and chemotaxis. PNO1 knockout also inhibited colony and spheroid formation, cell migration and invasion, and markers of stem cells, pluripotency and EMT in CSCs. Overall, our data suggest that PNO1 can be used as a diagnostic and prognostic biomarker of HCC, and knockout of PNO1 by CRISPR/Cas9 can be beneficial for the management of HCC by targeting CSCs.
Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Proteínas de Ligação a RNA , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Masculino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Feminino , Prognóstico , Pessoa de Meia-Idade , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Receptores Notch/metabolismo , Receptores Notch/genética , Movimento Celular/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transição Epitelial-Mesenquimal/genética , Proliferação de Células , Relevância ClínicaRESUMO
Growth is crucially controlled by the functional ribosomes available in cells. To meet the enhanced energy demand, cancer cells re-wire and increase their ribosome biogenesis. The RNA-binding protein PNO1, a ribosome assembly factor, plays an essential role in ribosome biogenesis. The purpose of this study was to examine whether PNO1 can be used as a biomarker for lung adenocarcinoma and also examine the molecular mechanisms by which PNO1 knockdown by CRISPR/Cas9 inhibited growth and epithelial-mesenchymal transition (EMT). The expression of PNO1 was significantly higher in lung adenocarcinoma compared to normal lung tissues. PNO1 expression in lung adenocarcinoma patients increased with stage, nodal metastasis, and smoking. Lung adenocarcinoma tissues from males expressed higher PNO1 than those from females. Furthermore, lung adenocarcinoma tissues with mutant Tp53 expressed higher PNO1 than those with wild-type Tp53, suggesting the influence of Tp53 status on PNO1 expression. PNO1 knockdown inhibited cell viability, colony formation, and EMT, and induced apoptosis. Since dysregulated signalling through the Notch receptors promotes lung adenocarcinoma, we measured the effects of PNO1 inhibition on the Notch pathway. PNO1 knockdown inhibited Notch signalling by suppressing the expression of Notch receptors, their ligands, and downstream targets. PNO1 knockdown also suppressed CCND1, p21, PTGS-2, IL-1α, IL-8, and CXCL-8 genes. Overall, our data suggest that PNO1 can be used as a diagnostic biomarker, and also can be an attractive therapeutic target for the treatment of lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Masculino , Feminino , Humanos , Sistemas CRISPR-Cas/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma/patologia , Receptores Notch/genética , Receptores Notch/metabolismo , Neoplasias Pulmonares/patologia , Ribossomos/metabolismo , Ribossomos/patologia , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence.
