Tumor-associated macrophage-derived transforming growth factor-β promotes colorectal cancer progression through HIF1-TRIB3 signaling.
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ABSTRACT:
SUBMITTER: Liu C
PROVIDER: S-EPMC8486199 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism.MethodsNLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry.ResultsNLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription.ConclusionsWe showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.
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Project description:The transforming growth factor beta (TGF-?) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colorectal cancer (CRC). The inactivation of TGFBR2 is the most common genetic event affecting the TGF-? signaling pathway. However, the mechanism by which cancer cells downregulate TGFBR2 is unclear. In this study, we found that the TGFBR2 protein levels were consistently upregulated in CRC tissues, whereas its mRNA levels varied in these tissues, suggesting that a post-transcriptional mechanism is involved in the regulation of TGFBR2. Because microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that potentially target TGFBR2. We identified the specific targeting site of miR-135b in the 3'-untranslated region (3'-UTR) of TGFBR2. We further identified an inverse correlation between the levels of miR-135b and TGFBR2 protein, but not mRNA, in CRC tissue samples. By overexpressing or silencing miR-135b in CRC cells, we experimentally validated that miR-135b directly binds to the 3'-UTR of the TGFBR2 transcript and regulates TGFBR2 expression. Furthermore, the biological consequences of the targeting of TGFBR2 by miR-135b were examined using in vitro cell proliferation and apoptosis assays. We demonstrated that miR-135b exerted a tumor-promoting effect by inducing the proliferation and inhibiting the apoptosis of CRC cells via the negative regulation of TGFBR2 expression. Taken together, our findings provide the first evidence supporting the role of miR-135b as an oncogene in CRC via the inhibition of TGFBR2 translation.
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Project description:Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6?3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation through recruitment of macrophages and endothelial cells. Moreover, ETP expression was associated with aggressive mammary tumor growth and high metastatic growth. These effects were partially mediated through enhanced TGF-? signaling, which contributes to tissue fibrosis and epithelial-mesenchymal transition (EMT) of tumor cells. Our results highlight the crucial role of ETP as an obesity-associated factor that promotes tumor growth in the context of adipocyte interactions with tumor and stromal cells.
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Project description:Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP-1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP-1 deficient (PARP-1-/-) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1-/- mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up-regulation. PARP-1-/- animals were then crossed with O6-methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1-/-/MGMT-/- double knockout (DKO) mice developed more, but much smaller tumors than MGMT-/- animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar O6-methylguanine levels. Studies with PARP-1-/- cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to O6-methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression.
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Project description:Bone marrow macrophages (BMMs) share common progenitors with osteoclasts and are critical components of bone-tumor microenvironment; however, their function in prostate tumor growth in the skeleton has not been explored. BMMs are the major source of inflammatory factors and proteases, including cysteine protease cathepsin K (CTSK). In this study, utilizing mice deficient in CTSK, we demonstrate the critical involvement of this potent collagenase in tumor progression in bone. We present the evidence that tumor growth and progression in the bone are impaired in the absence of CTSK. Most importantly, we show for the first time that BMM-supplied CTSK may be involved in CCL2- and COX-2-driven pathways that contribute to tumor progression in bone. Together, our data unravel novel roles for CTSK in macrophage-regulated processes, and provide evidence for close interplay between inflammatory, osteolytic and tumor cell-driven events in the bone-tumor microenvironment.
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Project description:BackgroundTumor-associated macrophages (TAMs) are key regulators of the complex interplay between cancer and the immune microenvironment. Tumor cell-derived spondin 2 (SPON2) is an extracellular matrix glycoprotein that has complicated roles in recruitment of macrophages and neutrophils during inflammation. Overexpression of SPON2 has been shown to promote tumor cell migration in colorectal cancer (CRC). However, the mechanism by which SPON2 regulates the accumulation of TAMs in the tumor microenvironment (TME) of CRC is unknown.MethodsImmunohistochemistry was used to examine SPON2 expression in clinical CRC tissues. In vitro migration assays, transendothelial migration assays (iTEM), and cell adhesion assays were used to investigate the effects of SPON2 on monocyte/macrophage migration. Subcutaneous tumor formation and orthotopic implantation assays were performed in C57 BL/6 mice to confirm the effects of SPON2 on TAM infiltration in tumors.ResultsSPON2 expression is positively correlated with M2-TAM infiltration in clinical CRC tumors and poor prognosis of CRC patients. In addition, SPON2 promotes cytoskeletal remodeling and transendothelial migration of monocytes by activating integrin β1/PYK2 axis. SPON2 may indirectly induce M2-polarization through upregulating cytokines including IL10, CCL2 and CSF1 expression in tumor cells. Blocking M2 polarization and Macrophage depletion inhibited the SPON2-induced tumors growth and invasion. Furthermore, blocking the SPON2/integrin β1/PYK2 axis impairs the transendothelial migration of monocytes and cancer-promoting functions of TAMs in vivo.ConclusionsOur findings demonstrate that SPON2-driven M2-TAM infiltration plays an important role during CRC tumor growth and metastasis. SPON2 may be a valuable biomarker guiding the use of macrophage-targeting strategies and a potential therapeutic target in advanced CRC.
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Project description:The immune response facilitated by tumor-associated macrophages is a vital determinant of tumor progression. We identified differentially expressed genes between various macrophage phenotypes in the Gene Expression Omnibus, and used Kaplan-Meier Plotter to determine which of them altered the prognosis of esophageal carcinoma patients. Fibrinogen-like protein 2 (FGL2), an immunosuppressive factor in the tumor microenvironment of various cancers, was upregulated in M2 macrophages, and higher FGL2 expression was associated with poorer survival in esophageal carcinoma patients. Using the TIMER database, we found that FGL2 expression correlated positively with the levels of immune markers of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in esophageal carcinoma samples. Correlation analyses in cBioPortal revealed that the mRNA levels of FGL2 correlated strongly with those of interleukin 10, matrix metalloproteinase 9, C-C motif chemokine ligand 5, T-cell immunoglobulin mucin 3, interleukin 13, vascular cell adhesion molecule 1, macrophage colony-stimulating factor and fibroblast growth factor 7 in esophageal carcinoma tissues. The same cytokines were upregulated when esophageal squamous cell carcinoma cells were co-cultured with M2-like tumor-associated macrophages. Thus, by secreting FGL2, M2-like tumor-associated macrophages may create an immunosuppressive tumor microenvironment that induces the occurrence and progression of esophageal carcinoma.
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Project description:High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.
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Project description:Previously, we reported a molecular mechanism by which Ahnak potentiates transforming growth factor-β (TGFβ) signaling during cell growth. Here, we show that Ahnak induces epithelial-mesenchymal transition (EMT) in response to TGFβ. EMT phenotypes, including altered in cell morphology, and expression patterns of various EMT marker genes were detected in HaCaT keratinocytes transfected with Ahnak-specific siRNA. Knockdown of Ahnak expression in HaCaT keratinocytes resulted in attenuated cell migration and invasion. We found that Ahnak activates TGFβ signaling via Smad3 phosphorylation, leading to enhanced Smad3 transcriptional activity. To validate function of Ahnak in EMT of B16F10 cells having high metastatic and tumorigenic properties, we established B16F10 cells with stable knockdown of Ahnak. N-cadherin expression and Smad3 phosphorylation were significantly decreased in B16F10-shAhnak cells, compared to B16F10-shControl cells after treatment of TGFβ. Moreover, TGFβ failed to induce cell migration and cell invasion in B16F10-shAhnak cells. To determine whether Ahnak regulates the metastatic activity of B16F10 cells, we established a lung metastasis model in C57BL/6 mice via tail vein injection of B16F10-shAhnak cells. Lung metastasis was significantly suppressed in mice injected with B16F10-shAhnak cells, compared to those injected with B16F10-shControl cells. Taken together, we propose that TGFβ-Ahnak signaling axis regulates EMT during tumor metastasis.
| S-EPMC6158194 | biostudies-literature
Project description:Rationale: Tumor-associated macrophages (TAMs), generally displaying the pro-tumor M2-like phenotype, strongly influence the progression of colorectal cancer (CRC) via their immunosuppressive activities. The high-mobility gene group A2 (HMGA2), an oncoprotein, is aberrantly overexpressed in CRC cells. However, the mechanisms by which tumor-derived HMGA2 modulates tumor microenvironment in CRC remain poorly understood. Methods: In vivo subcutaneous tumor xenograft model, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model and in vitro co-culture assays were used to investigate the Hmga2 role in TAM recruitment and polarization. Luciferase and chromatin immunoprecipitation (ChIP) assays were applied to examine the mechanism of HMGA2-mediated transcriptional regulation of signal transducer and activator of transcription 3 (STAT3). The CD68 correlation with patient outcome was analyzed in 167 human CRC tissues. Results: We found that HMGA2 in cancer cells promoted macrophage recruitment and M2 polarization in vitro and in vivo. HMGA2 directly bound to the STAT3 promoter to activate its transcription and subsequently induced CCL2 secretion, thus promoting macrophage recruitment. Our results from human CRC specimens also revealed a strong positive association between HMGA2 expression in tumor cells and CD68 expression in the stroma. We further showed that patients with an elevated CD68 expression had an unfavorable overall survival in all of the patients or in the subgroup with negative distant metastasis. Conclusion: Our work uncovers new insight into the link between the HMGA2/STAT3/CCL2 axis and macrophage recruitment in CRC. These findings provide a novel therapeutic option for targeting the HMGA2/STAT3/CCL2 axis in CRC.
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