Dataset Information

FAIM2 Promotes Non-Small Cell Lung Cancer Cell Growth and Bone Metastasis by Activating the Wnt/β-Catenin Pathway.

ABSTRACT:

Aim

Bone metastasis is the major reason for the poor prognosis and high mortality rate of non-small cell lung cancer (NSCLC) patients. This study explored the function and underlying mechanism of Fas apoptotic inhibitory molecule 2 (FAIM2) in the bone metastasis of NSCLC.

Methods

Samples of normal lung tissue and NSCLC tissue (with or without bone metastasis) were collected and analyzed for FAIM2 expression. HARA cells with FAIM2 overexpression and HARA-B4 cells with FAIM2 knockdown were tested for proliferation, migration, invasion, anoikis, and their ability to adhere to osteoblasts. Next, whether FAIM2 facilitates bone metastasis by regulating the epithelial mesenchymal transformation (EMT) process and Wnt/β-catenin signaling pathway were investigated. Finally, an in vivo model of NSCLC bone metastasis was established and used to further examine the influence of FAIM2 on bone metastasis.

Results

FAIM2 was highly expressed in NSCLC tissues and NSCLC tissues with bone metastasis. FAIM2 expression was positively associated with the tumor stage, lymph node metastasis, bone metastasis, and poor prognosis of NSCLC. FAIM2 upregulation promoted HARA cell proliferation, migration, and invasion, but inhibited cell apoptosis. FAIM2 knockdown in HARA-B4 cells produced the opposite effects. HARA-B4 cells showed a stronger adhesive ability to osteocytes than did HARA cells. FAIM2 was found to be related to the adhesive ability of HARA and HARA-B4 cells to osteocytes. FAIM2 facilitated bone metastasis by regulating the EMT process and Wnt/β-catenin signaling pathway. Finally, FAIM2 was found to participate in regulating NSCLC bone metastasis in vivo.

Conclusions

FAIM2 promoted NSCLC cell growth and bone metastasis by regulating the EMT process and Wnt/β-catenin signaling pathway. FAIM2 might be useful for diagnosing and treating NSCLC bone metastases.

SUBMITTER: She K

PROVIDER: S-EPMC8459617 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundWnt2 is overexpressed and able to promote tumorigenesis in many types of cancer. However, its expression and role in lung cancer has not been well clarified yet. In this study, we aims to investigate the expression pattern, clinical significance and the underlying molecular mechanism of Wnt2 in non-small lung cancer (NSCLC).MethodsImmunohistochemical staining and ELISA assays were applied to detect Wnt2 level in tumor tissue and serum. EDU incorporation assays and colony formation assays were used to evaluate the growth-promoting effect of Wnt2 in vitro. Then we performed western blot and immunofluorescence assays to detect the activation of WNT signaling pathway. Finally mice engrafted with NSCLC tumor cells were used to assess the role of Wnt2 in vivo.ResultsImmunohistochemical staining consisting of 264 NSCLC tumor tissues showed that a high level of Wnt2 was associated with a poor overall survival (OS) and relapse-free survival (RFS) of NSCLC patients (P = 0.002 and 0.0005, respectively). Multivariate analysis presented that Wnt2 level in tumor tissue was an independent prognostic factor (P = 0.049 for OS and P = 0.002 for RFS, respectively). Furthermore, ELISA assays for 181 individuals (116 NSCLC and 65 controls) revealed that serum Wnt2 levels in adenocarcinoma was significantly higher than that in healthy volunteers (P < 0.0001). In vitro H460 cell line stably overexpressing Wnt2 showed enhanced growth activity than the control cells whereas knockdown of Wnt2 by siRNA in H1299 cells resulted in decreased growth activity. Additionally, Wnt2 level in tumor tissues was significantly associated with Ki-67 level (rs: 0.316; P < 0.0001). Immunofluorescence and Western blot assays detected the translocation of β-catenin from cytoplasm into nucleus, which indicated that Wnt2 probably promotes proliferation by activating WNT/β-catenin pathway. In vivo H460 cells expressing exogenous Wnt2 showed increased growth-promoting effect in Balb/c nude mice than control cells.ConclusionsThe present study for the first time suggested that Wnt2 was both a prognostic and a diagnostic biomarker for NSCLC. Tumor-derived Wnt2 can promote growth activity of NSCLC cells through activating WNT/β-catenin signaling pathway.

Project description:Breast cancer has become the malignant disease with the highest morbidity and mortality among female cancer patients. The prognosis of metastatic breast cancer is very poor, and the therapeutic effects still need to be improved. The molecular mechanism of breast cancer has not been fully clarified. Bioinformatics analysis was used to find the differentially expressed gene that affects the occurrence and development of breast cancer. Furthermore, scratch assays, Transwell assays, immunofluorescence, and Western blotting were used to determine the biological behavior of breast cancer cells affected by DEP domain-containing protein 1B (DEPDC1B). The molecular mechanism was investigated by mass spectrometry analysis, coimmunoprecipitation, and ubiquitin assays. Here, we found that DEPDC1B was highly expressed in breast cancer cells and tissues and was associated with lower overall survival (OS) in patients. We found that DEPDC1B interference significantly inhibited tumor invasion and migration in vitro and tumor metastasis in vivo. Mechanistically, DEPDC1B was first shown to activate the wnt/β-catenin signaling pathway as an oncogene in breast cancer cells. In addition, we also confirmed the interaction between DEPDC1B, ubiquitin-specific protease 5 (USP5), and β-catenin. Then, we found that DEPDC1B mediates the deubiquitination of β-catenin via USP5, which promotes cell invasion and migration. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be considered a potential therapeutic target for breast cancer.NEW & NOTEWORTHY By using bioinformatics analysis and the experimental techniques of cell biology and molecular biology, we found that DEP domain-containing protein 1B (DEPDC1B) can promote the invasion and migration of breast cancer cells and that DEPDC1B mediates the deubiquitination of β-catenin by ubiquitin-specific protease 5 (USP5), thus activating the wnt/β-catenin pathway. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be used as a potential therapeutic target for breast cancer.

Project description:Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENT Mutations in the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.