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Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1.

ABSTRACT: Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1-/- Trp53-/- SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin β1, which stabilized integrin β1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin β1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin β1 turnover in controlling SCLC metastasis, which might have therapeutic implications.

SUBMITTER: Zhao G

PROVIDER: S-EPMC6391098 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer.

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| S-EPMC4833874 | biostudies-literature

Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer.

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| S-EPMC4049383 | biostudies-literature

Deubiquitinase USP5 promotes non-small cell lung cancer cell proliferation by stabilizing cyclin D1.

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| S-EPMC8577967 | biostudies-literature

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| S-EPMC2994222 | biostudies-other

Nrf2 Deficiency Promotes Melanoma Growth and Lung Metastasis.

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LncRNA AWPPH participates in the metastasis of non-small cell lung cancer by upregulating TGF-β1 expression.

Project description:Long non-coding RNA (lncRNA) AWPPH is a characterized oncogenic lncRNA in hepatocellular carcinoma and bladder cancer. The aim of the present study was to investigate the potential involvement of AWPPH in non-small cell lung cancer (NSCLC). Expression of AWPPH in lung biopsy tissues and serum of both healthy controls and patients with NSCLC with different tumor sizes, and with and without distant tumor metastasis was detected by reverse transcription-quantitative PCR. AWPPH expression vector was constructed and transfected into cells of human NSCLC cell lines. Expression of TGF-β1 was detected by western blot analysis. Cell migration and invasion were detected by Transwell migration and invasion assay. It was observed that AWPPH was significantly upregulated in patients with NSCLC, while AWPPH expression level did not increase with the increase of tumor size. In contrast, AWPPH expression levels were significantly higher in patients with distant metastasis than in patients without tumor distant metastasis. AWPPH overexpression promoted TGF-β1 expression in NSCLC cells, while TGF-β1 treatment showed no significant effects on AWPPH expression. AWPPH overexpression promoted NSCLC cell migration and invasion, while TGF-β signaling inhibition reduced this enhancing effect. Therefore, AWPPH may promote the metastasis, but not the growth of NSCLC by upregulating TGF-β1 expression.

| S-EPMC6732945 | biostudies-literature

PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of oral squamous cell carcinoma via activation of integrin β1.

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Nogo-B receptor is required for stabilizing TGF-β type I receptor and promotes the TGF-β1-induced epithelial-to-mesenchymal transition of non-small cell lung cancer.

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| S-EPMC7778533 | biostudies-literature

CD47 Promotes Tumor Invasion and Metastasis in Non-small Cell Lung Cancer.

Project description:CD47 is overexpressed in many human cancers, its level positively correlates with tumor invasion and metastasis. However, it is largely unknown whether CD47 overexpression drives metastasis and how CD47 lead to tumor metastasis in non-small cell lung cancer (NSCLC). In this study, we analyzed NSCLC specimens and cell lines, and revealed that CD47 is expressed at a higher level than in tumor-free control samples. Furthermore, increased CD47 expression correlated with clinical staging, lymph node metastasis and distant metastasis. In order to understand the molecular mechanisms underlying CD47 functions, we applied both gain-of-function and loss-of-function approaches in cell lines. The siRNA-mediated downregulation of CD47 inhibited cell invasion and metastasis in vitro, while the overexpression of CD47 by plasmid transfection generated opposite effects. In vivo, CD47-specific shRNA significantly reduced tumor growth and metastasis. On the molecular level, the expression of CD47 correlated with that of Cdc42, both in cell lines and NSCLC specimens. The inhibition of Cdc42 attenuates the invasion and metastasis of CD47-overexpressing cells. These results indicate that Cdc42 is a downstream mediator of CD47-promoted metastasis. Our findings provide first evidence that CD47 is an adverse prognostic factor for disease progression and metastasis, and a promising therapeutic target for NSCLC.

| S-EPMC4944213 | biostudies-literature

DDX24 promotes metastasis by regulating RPL5 in non-small cell lung cancer.

Project description:PurposeNon-small cell lung cancer (NSCLC) is a leading cause of cancer death, and metastasis is a crucial determinant of increased cancer mortality. DDX24 has garnered increased attention due to its correlation with tumorigenesis and malignant progression. However, the correlation between DDX24 and NSCLC remains unclear.MethodsDDX24 expression in NSCLC tissues and survival rate of patients was analyzed using bioinformatic analysis. Transwell assays, wound-healing assays, and tail vein lung colonization models were employed to determine the role of DDX24 in migration and invasion in vitro and in vivo. We searched for DDX24-interacting proteins using co-immunoprecipitation followed by mass spectroscopy and verified the interaction. The influence of DDX24 on RPL5 expression and ubiquitination was examined using protein stability assays.ResultsDDX24 expression was upregulated in NSCLC cell lines and tumors of patients, particularly those with high tumor grades. A high DDX24 level was also correlated with a poor prognosis. DDX24 upregulation enhanced the migration and invasion ability of NSCLC cells, whereas its downregulation had the opposite effects. In vivo xenograft experiments confirmed that tumors with high DDX24 expression had higher metastatic abilities. The interaction between DDX24 and RPL5 promoted its ubiquitination and destabilized it.ConclusionsDDX24 acted as a pro-tumorigenic factor and promoted metastasis in NSCLC. DDX24 interacted with RPL5 to promote its ubiquitination and degradation. As a result, targeting DDX24/RPL5 axis may provide a novel potential therapeutic strategy for NSCLC.

| S-EPMC9741967 | biostudies-literature

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