Cathepsin C regulates tumor progression via the Yes-associated protein signaling pathway in non-small cell lung cancer
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ABSTRACT:
SUBMITTER: Kim N
PROVIDER: S-EPMC10839315 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Lung cancer remains the most lethal cancer worldwide because of its high metastasis potential. Epithelial-mesenchymal transition (EMT) is known as the first step of the metastasis cascade, but the potential regulatory mechanisms of EMT have not been clearly established. In this study, we first found that low CUEDC1 expression correlated with lymph node metastasis in non-small cell lung cancer (NSCLC) patients using immunohistochemistry (IHC). CUEDC1 knockdown promoted the metastasis of NSCLC cells and EMT process and activated TβRI/Smad signaling pathway. Overexpression of CUEDC1 decreased the metastatic potential of lung cancer cells and inhibited the EMT process and inactivated TβRI/Smad signaling pathway. Immunoprecipitation (IP) assays showed that Smurf2 is a novel CUEDC1-interacting protein. Furthermore, CUEDC1 could regulate Smurf2 expression through the degradation of Smurf2. Overexpression of Smurf2 abolished CUEDC1 knockdown induced-EMT and the activation of TβRI/Smad signaling pathway, while siRNA Smurf2 reversed CUEDC1 overexpression-mediated regulation of EMT and TβRI/Smad signaling pathway. Additionally, CUEDC1 inhibited proliferation and promoted apoptosis of NSCLC cells. In vivo, CUEDC1-knockdown cells promoted metastasis and tumor growth compared with control cells. In conclusion, our findings indicate that the crucial role of CUEDC1 in NSCLC progression and provide support for its clinical investigation for therapeutic approaches.
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Project description:Lung cancer is the leading cause of cancer-related death worldwide. KLHL38 has been reported to be upregulated during diapause but downregulated after androgen treatment during the reversal of androgen-dependent skeletal muscle atrophy. This study aimed to clarify the role of KLHL38 in non-small cell lung cancer (NSCLC). KLHL38 expression was evaluated in tumor and adjacent normal tissues from 241 patients with NSCLC using immunohistochemistry and real-time PCR, and its association with clinicopathological parameters was analyzed. KLHL38 levels positively correlated with tumor size, lymph node metastasis, and pathological tumor-node-metastasis stage (all P < 0.001). In NSCLC cell lines, KLHL38 overexpression promoted PTEN ubiquitination, thereby activating Akt signaling. It also promoted cell proliferation, migration, and invasion by upregulating the expression of genes encoding cyclin D1, cyclin B, c-myc, RhoA, and MMP9, while downregulating the expression of p21 and E-cadherin. In vivo experiments in nude mice further confirmed that KLHL38 promotes NSCLC progression through Akt signaling pathway activation. Together, these results indicate that KLHL38 is a valuable candidate prognostic biomarker and potential therapeutic target for NSCLC.
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Project description:BackgroundNon-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most lethal tumour worldwide. Copine 1 (CPNE1) was identified as a novel oncogene in NSCLC in our previous study. However, its specific function and relative mechanisms remain poorly understood.MethodsThe biological role of CPNE1 and RACK1 in NSCLC was investigated using gene expression knockdown and overexpression, cell proliferation assays, clonogenic assays, and Transwell assays. The expression levels of CPNE1, RACK1 and other proteins were determined by western blot analysis. The relationship between CPNE1 and RACK1 was predicted and investigated by mass spectrometry analysis, immunofluorescence staining, and coimmunoprecipitation. NSCLC cells were treated with a combination of a MET inhibitor and gefitinib in vitro and in vivo.ResultsWe found that CPNE1 facilitates tumorigenesis in NSCLC by interacting with RACK1, which further induces activation of MET signaling. CPNE1 overexpression promoted cell proliferation, migration, invasion and MET signaling in NSCLC cells, whereas CPNE1 knockdown produced the opposite effects. In addition, the suppression of the enhancing effect of CPNE1 overexpression on tumorigenesis and MET signaling by knockdown of RACK1 was verified. Moreover, compared to single-agent treatment, dual blockade of MET and EGFR resulted in enhanced reductions in the tumour volume and downstream signaling in vivo.ConclusionsOur findings show that CPNE1 promotes tumorigenesis by interacting with RACK1 and activating MET signaling. The combination of a MET inhibitor with an EGFR-TKI attenuated tumour growth more significantly than either single-drug treatment. These findings may provide new insights into the biological function of CPNE1 and the development of novel therapeutic strategies for NSCLC. Video Abstract.
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Project description:BackgroundThe treatment of non-small cell lung cancer (NSCLC) is challenging due to immune tolerance and evasion. Salidroside (SAL) is an extract in traditional Chinese medicine and has a potential antitumor effect. However, the mechanism of SAL in regulating the immunological microenvironment of NSCLC is yet to be clarified.MethodsThe mouse model with Lewis lung cancer cell line (3LL) in C57BL/6 mice was established. And then, the percentage of tumor-infiltrating T cell subsets including Treg was detected in tumor-bearing mice with or without SAL treatment. In vitro, the effect of SAL on the expression of IL-10, Foxp3 and Stub1 and the function of Treg were detected by flow cytometry. Network pharmacology prediction and molecular docking software were used to predict the target of SAL and intermolecular interaction. Furthermore, the effect of SAL on the expression of Hsp70 and the co-localization of Stub1-Foxp3 in Treg was confirmed by flow cytometry and confocal laser microscopy. Finally, Hsp70 inhibitor was used to verify the above molecular expression.ResultsWe discovered that SAL treatment inhibits the growth of tumor cells by decreasing the percentage of tumor-infiltrated CD4+Foxp3+T cells. SAL treatment downregulates the expression of Foxp3 in Tregs, but increases the expression of Stub1, an E3 ubiquitination ligase upstream of Foxp3, and the expression of Hsp70. Inhibiting the expression of Hsp70 reverses the inhibition of SAL on Foxp3 and disrupts the colocalization of Stub1 and Foxp3 in the nucleus of Tregs.ConclusionsSAL inhibits tumor growth by regulating the Hsp70/stub1/Foxp3 pathway in Treg to suppress the function of Treg. It is a new mechanism of SAL for antitumor therapy.
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Project description:Background: Long non-coding RNAs have been reported to be involved in tumorigenesis and progression through different regulatory mechanisms. It has been reported that aberrantly expressed long non-coding RNA LINC00491 promotes malignancy in multiple tumors, while the role of LINC00491 in lung adenocarcinoma (LUAD) is little reported and the mechanism for regulating tumor progression has not been elucidated. Methods: RNA sequencing and the TCGA database were combined to screen differentially expressed lncRNAs that facilitate tumor progression. The expression level of LINC00491 was examined in LUAD clinical samples and in cell lines using RT-qPCR. In vitro experiments including colony formation assay, EdU assay, cell migration and invasion assay and wound healing assay, and in vivo experiments including xenografting subcutaneous tumors and lung metastasis models were performed to investigate the function of LINC00491 in LUAD tumor progressions. RNA pull-down, mass spectrometry, RIP assays and truncation experiments were carried out to explore the proteins binding to LINC00491 and the specific interactions between the RNA-protein complex. Results: Our results showed that LINC0491 was significantly upregulated in LUAD and positively correlated with poor survival. High LINC00491 expression promoted proliferation, migration and invasion, and resulted in a high metastatic burden in LUAD. Using pull-down assay and mass spectrometry, MTSS1 was found binding to LINC00491, and the conducted experiments verified the direct interaction between LINC00491 and MTSS1. Meanwhile, LINC00491 was found to regulate MTSS1 degradation by promoting the MTSS1 ubiquitination level and then activating the Wnt/β-catenin-signaling pathway. LINC00491/MTSS1/β-catenin may act as a complex to facilitate tumor progression. Conclusions: In summary, our results found a novel mechanism in which LINC00491 directly interacts with MTSS1 by affecting its ubiquitination modification to promote LUAD proliferation, migration and invasion, then activating the Wnt/β-catenin-signaling pathway, demonstrating its significant role in tumor progression and suggesting that the LINC00491/MTSS1/Wnt/β-catenin-signaling pathway could serve as a potential therapeutic target for lung adenocarcinoma in the future.
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Project description:BackgroundLung adenocarcinoma (LUAD) is a heavy social burden worldwide. Because the mechanisms involved in LUAD remain unclear, the prognosis of LUAD remains poor. Consequently, it is urgent to investigate the potential mechanisms of LUAD. Junctional adhesion molecule-like protein (JAML), is recognized as a tumorigenesis molecule in gastric cancer. However, the role of JAML in LUAD is still unclear. Here we aimed to evaluate the role of JAML in LUAD.MethodsqRT-PCR, Western blotting and immunohistochemistry were conducted to investigate the expression of JAML in LUAD tissues. JAML was knocked down and overexpressed in LUAD cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Proliferation potential of LUAD cells were detected by Cell Counting Kit-8, EdU incorporation and Colony formation assay. Migration and invasion abilities of LUAD cells were determined by wound healing, transwell migration and invasion assays. Cell cycle and cell apoptosis were detected by flow cytometry. The effects of JAML in vivo were studied in xenograft tumor models. Western blotting was used to explore the molecular mechanisms of JAML function. In addition, rescue experiments were performed to verify the possible mechanisms.ResultsJAML expression was elevated in LUAD tissues compared with peritumor tissues, and this upregulation was positively related to pT and pTNM. Furthermore, both in vitro and in vivo, JAML silencing markedly repressed malignant behaviors of LUAD cells and vice versa. Knockdown of JAML also mediated cell cycle arrest at G0/G1 phase and promoted apoptosis in LUAD cells. Mechanistically, silencing JAML repressed the process of epithelial-mesenchymal transition by inactivating the Wnt/β-catenin pathway in LUAD cells. Effects of JAML can be rescued by Wnt/β-catenin pathway activator in A549 cells.ConclusionsOur data reveal the oncogenic role of JAML in LUAD, indicating that JAML may be a predictive biomarker and novel therapeutic target for LUAD.
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