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  2. College of Medicine / 醫學院
  3. Clinical Laboratory Sciences and Medical Biotechnology / 醫學檢驗暨生物技術學系所
  4. Mechanisms of Tumor Associated Macrophage-altered Cancer Progression and SPANXA-mediated Metastatic Suppression in Lung Cancer
 
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Mechanisms of Tumor Associated Macrophage-altered Cancer Progression and SPANXA-mediated Metastatic Suppression in Lung Cancer

Date Issued
2016
Date
2016
Author(s)
Hsiao, Yi-Jing
DOI
10.6342/NTU201601066
URI
http://ntur.lib.ntu.edu.tw//handle/246246/277440
Abstract
Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. M1 macrophage is associated with favorable outcome of lung cancer patients clinically. Herein, we discover the different macrophages’ influences on lung cancer cell. We found M2a/M2c subtypes promote A549 invasion and xenograft tumor growth. The M1 subtype suppressed angiogenesis. M1 enhanced the sensitivity of A549 to cisplatin and decreased the tube formation activity and cell viability of A549 cells by inducing apoptosis and senescence. By expression microarray, we identified the impacts from different macrophage subtypes on A549. The regulated genes were involved in the immune response, cytoskeletal remodeling, coagulation, cell adhesion, and apoptosis pathways in A549 cells. The identified M1/M2 gene signatures were significantly correlated with the extended overall survival of lung cancer patients. Administration of M1 conditioned media (CM) to A549-bearing mice significantly reduced the tumor size. Microarray analysis indicated that p53 was a critical regulator in M1-treated A549. M1 CM induced cell apoptosis and enhanced wt-p53 accumulation. Furthermore, M1 prolonged p53 protein stability by reducing its ubiquitination. Next, we revealed that STAT1 is a key mediator for p53 accumulation. STAT1 was up-regulated and activated upon M1 CM stimulation. STAT1 reduced p53 ubiquitination and knockdown STAT1 reversed the increase of p53 stability. The interaction of STAT1 and p53 was enhanced by M1 CM, but it was reduced by STAT1-Y701F. Inhibiting STAT1 activation or silencing the IFNAR2, JAK1 and TYK2 inhibited M1-induced apoptosis. Taken together, STAT1 signaling is required for M1 CM-induced apoptosis through p53 accumulation. The M1 CM-induced apoptosis was IFN-γ-independent. Our findings imply that M1 macrophages play an important role in the immune surveillance for cancer progression by inducing STAT1 activation and p53 accumulation in lung cancers. SPANXA (Sperm Protein Associated with the Nucleus on the X-chromosome family, A1/A2) is identified as a cancer-testis antigens expressed in normal testis but dysregulated in various tumors. It plays unknown roles in spermiogenesis and cancer progression. We discovered SPANXA highly expressed in the low-invasive CL1-0 cells compared with the isogenous high-invasive CL1-5 cells. Herein, we investigated the role of SPANXA in metastasis of lung adenocarcinoma. SPANXA was preferably expressed in tumor tissues and associated with the prolonged survival of lung cancer patients. SPANXA suppressed the invasion and metastasis of lung cancer cells in vitro and in vivo. By the expression microarray and pathway analysis, we found that the SPANXA-altered genes were enriched in the epithelial–mesenchymal transition (EMT) pathway. The cell plasticity undergoes MET while SPANXA expresses. Slug is an important transcription factor in lung cancer progression and also an EMT inducer which represses E-cadherin, a protein maintaining cell-cell adherin. SPANXA reduced Slug expression resulted in up-regulating E-cadherin. Furthermore, the restoration or inhibition of Slug could reverse the invasive suppression of SPANXA. c-JUN acts as the positive-regulator of EMT. Silencing SPANXA increased c-JUN mRNA expression and blockage of c-JUN led to SNAI2 down-regulation. We also discovered that the Lamin A/C decreased and E-cadherin increased in the nucleus. Our results clearly characterized SPANXA as an EMT inhibitor by suppressing c-JUN-SNAI2 axis in lung adenocarcinoma.
Subjects
TAM
M1 macrophage
apoptosis
EMT
lung adenocarcinoma
SDGs

[SDGs]SDG3

Type
thesis
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