FAM171B stabilizes vimentin and enhances CCL2-mediated TAM infiltration to promote bladder cancer progression

Abstract

Background Invasion and metastasis are the main causes of unfavourable prognosis in patients diagnosed with bladder cancer. The efficacy of immunotherapy in bladder cancer remains suboptimal due to the presence of an immunosuppressive microenvironment. The novel protein family with sequence similarity 171B (FAM171B) has been identified, but its precise role and mechanism in bladder cancer remain unclear. Methods In this study, we conducted an analysis to investigate the associations between FAM171B expression and the prognosis and clinicopathological stage of bladder cancer. To this end, we utilized RNA sequencing data from the TCGA and GEO databases, as well as tumor tissue specimens obtained from our clinical centre. RNA sequencing analysis allowed us to examine the biological function of FAM171B at the transcriptional level in bladder cancer cells. Additionally, we used immunoprecipitation and mass spectrometry to identify the protein that interacts with FAM171B in bladder cancer cells. The effects of FAM171B on modulating tumor-associated macrophages (TAMs) and vimentin-mediated tumor progression, as well as the underlying mechanisms, were clarified by phalloidin staining, immunofluorescence staining, ELISA, RNA immunoprecipitation, flow cytometry and a bladder cancer graft model. Results FAM171B expression exhibits strong positive correlation with poor survival outcomes and advanced clinicopathological stages in patients with bladder cancer. FAM171B significantly promoted bladder cancer growth and metastasis, accompanied by TAM accumulation in the microenvironment, in vivo and in vitro. Through studies of the molecular mechanism, we found that FAM171B contributes to tumor progression by stabilizing vimentin in the cytoplasm. Additionally, our research revealed that FAM171B enhances the splicing of CCL2 mRNA by interacting with heterogeneous nuclear ribonucleoprotein U (HNRNPU), ultimately leading to increased recruitment and M2 polarization of TAMs. Conclusions In this study, we identified FAM171B as a potent factor that promotes the progression of bladder cancer. These findings establish a solid theoretical foundation for considering FAM171B as a potential diagnostic and therapeutic biomarker for bladder cancer.

LINC01559 promotes lung adenocarcinoma metastasis by disrupting the ubiquitination of vimentin

“…As an intermediate filament protein, vimentin is primarily expressed in mesenchymal cells, regulating cell shape, adhesion, and migration through its interactions with other proteins and its role in maintaining cytoskeletal structure, under physiological conditions [ 33 , 34 , 48 – 50 ]. Nevertheless, as we shown in LUAD cells in this study, vimentin expression is often upregulated in cancer cells, in particular, in those that have undergone the EMT [ 35 ].…”

Biological functions and clinic significance of SAF‑A (Review)

“…Zhang et al ( 74 ) found that SAF-A also binds to P-element-induced wimpy testis-interacting RNA-1742 (piRNA-1742) to stabilize USP8 mRNA and promote the progression of renal cell carcinoma. Through interaction with a family with sequence similarity 171 B (an independent prognostic factor for bladder cancer progression), SAF-A regulates the CCL2 pathway to facilitate M2 macrophage polarization in the tumor microenvironment, thereby promoting bladder cancer development ( 75 ).…”

Strategies for Overcoming Immune Evasion in Bladder Cancer

“…Compositions of chemokines within the TME substantially shape the direction and characteristics of macrophages. Specifically, chemokine (C-C motif) ligand 2 (CCL2) plays a crucial role in recruiting TAMs and contributes to bladder cancer cell proliferation, metastasis, and the establishment of an immunosuppressive environment in the TME [ 102 , 103 ]. Infiltrating TAMs can promote tumor development by altering the microenvironment of bladder cancer through the action of C-X-C motif chemokine ligand 8 (CXCL8) [ 103 ].…”

“…CCL2, a significant chemokine crucial for macrophages, exhibits high expression within cancer cells. It is actively secreted by these cells [ 102 ]. Several research studies have shown that CCL2 can promote the M2 polarization of TAMs, consequently amplifying immunosuppressive properties within the TME [ 180 , 181 ].…”

“…Several research studies have shown that CCL2 can promote the M2 polarization of TAMs, consequently amplifying immunosuppressive properties within the TME [ 180 , 181 ]. It has been found that CCL2 overexpression in bladder cancer is due to the FAM171B protein, which can act as an immune regulator and upregulate CCL2 expression [ 102 ]. Altering the immune microenvironment within tumors by targeting FAM171B could potentially serve as a viable strategy to increase the efficacy of immunotherapy when managing bladder cancer ( Figure 2 ).…”