Surfactant Protein B Suppresses Lung Cancer Progression by Inhibiting Secretory Phospholipase A2 Activity and Arachidonic Acid Production

Lee, Sung-Min; Kim, Daehoon; Kang, JiHoon; Kim, EunGi; Kim, Wanyeon; Youn, HyeSook; Youn, BuHyun

doi:10.1159/000479418

Cited by 31 publications

(19 citation statements)

References 72 publications

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“…There are data, however, which suggest a favorable role of surfactant in primary lung cancer. Recent studies suggest that surfactant proteins A and B are able to suppress the progression in NSCLC (45,46), possibly through interaction with immune cells (46,47) or by reducing the activity of EGFR and thereby acting in a similar manner to tyrosine-kinase inhibitors (48). The role of NAPSA in lung cancer is much less established, but recent studies suggest that NAPSA could have a supportive function with regards to the effect of EGFR tyrosine kinase inhibitors (49).…”

Section: Discussionmentioning

confidence: 99%

Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases that Correlates with Prolonged Survival

Pocha

Möck

Rapp

et al. 2020

Clinical Cancer Research

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Purpose: To provide a better understanding of the interplay between the immune system and brain metastases to advance therapeutic options for this life-threatening disease.Experimental Design: Tumor-infiltrating lymphocytes (TIL) were quantified by semiautomated whole-slide analysis in brain metastases from 81 lung adenocarcinomas. Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single-cell resolution. Molecular determinants of the extent of TILs in brain metastases were analyzed by transcriptomics in a subset of 63 patients. Findings in lung adenocarcinoma brain metastases were related to published multi-omic primary lung adenocarcinoma The Cancer Genome Atlas data (n ¼ 230) and single-cell RNA-sequencing (scRNA-seq) data (n ¼ 52,698).Results: TIL numbers within tumor islands was an independent prognostic marker in patients with lung adenocarcinoma brain metastases. Comparative transcriptomics revealed that expression of three surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) was closely associated with TIL numbers. Their expression was not only prognostic in brain metastasis but also in primary lung adenocarcinoma. Correlation with scRNA-seq data revealed that brain metastases with high expression of surfactant genes might originate from tumor cells resembling alveolar type 2 cells. Methylome-based estimation of immune cell fractions in primary lung adenocarcinoma confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment.Conclusions: The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) defines an inflamed subtype of lung adenocarcinoma brain metastases characterized by high abundance of TILs in close vicinity to tumor cells, a prolonged survival, and a tumor microenvironment which might be more accessible to immunotherapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases that Correlates with Prolonged Survival

Pocha

Möck

Rapp

et al. 2020

Clinical Cancer Research

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“…Although this has not been reported in other cancer types, further studies are required to determine how phosphatidylinositol synthase might regulate EMT in cancer cells. Eicosanoids are bioactive lipids derived from arachidonic acids and they have been suggested as promising targets for anti-cancer therapies [108]. Eicosanoids are produced by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) from arachidonic acid and each lipid derivative activates various cellular signaling pathways [109].…”

Section: Lipid Metabolism In Emtmentioning

confidence: 99%

Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

Kang

Kim

Lee

et al. 2019

IJMS

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120

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Activation of epithelial–mesenchymal transition (EMT) is thought to be an essential step for cancer metastasis. Tumor cells undergo EMT in response to a diverse range of extra- and intracellular stimulants. Recently, it was reported that metabolic shifts control EMT progression and induce tumor aggressiveness. In this review, we summarize the involvement of altered glucose, lipid, and amino acid metabolic enzyme expression and the underlying molecular mechanisms in EMT induction in tumor cells. Moreover, we propose that metabolic regulation through gene-specific or pharmacological inhibition may suppress EMT and this treatment strategy may be applied to prevent tumor progression and improve anti-tumor therapeutic efficacy. This review presents evidence for the importance of metabolic changes in tumor progression and emphasizes the need for further studies to better understand tumor metabolism.

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“…Radiation therapy is known to be an important approach for the treatment of NSCLC, but the obstacle of radiation resistance has a negative effect on the survival of patients with NSCLC [23]. Recently, several studies have suggested that miRNAs play a role in the radiation resistance of NSCLC by interacting with tumor-related genes [24, 25].…”

Section: Discussionmentioning

confidence: 99%

MiR-99a Enhances the Radiation Sensitivity of Non-Small Cell Lung Cancer by Targeting mTOR

Yin

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Radiation therapy is an important and effective modality for the treatment of non-small cell lung cancer (NSCLC). MicroRNAs (miRNAs) are crucial post-transcriptional regulators that are involved in numerous important biologic processes. However, their potential involvement in radiation sensitivity remains unknown. Materials: We performed integrated analysis of miRNA expression in NSCLC using The Cancer Genome Atlas datasets. miR-99a was found to be significantly upregulated in cancer tissue and regulated cell survival. Cell culture was used to assess the role of miR-99a in radiation sensitivity. We then used flow cytometry to examine the effects of miR-99a on the cell cycle and apoptosis in cells exposed to radiation. To identify gene targets of miR-99a, a bioinformatics approach was adopted, and the findings of this analysis were verified using luciferase reporter assays. Finally, an in vivo study was conducted to examine the effect of miR-99a on tumor volume in an NSCLC mouse model undergoing radiation therapy. Results: miR-99a was significantly upregulated in radiation-sensitive A549 cells compared with radiation-resistant A549 cells. miR-99a overexpression was shown to enhance radiosensitivity, while inhibition of miR-99a resulted in radioresistance of NSCLC cell lines in vitro and in vivo. In addition, by bioinformatics software analysis and luciferase assays, mammalian target of rapamycin (mTOR) was identified as a direct target of miR-99a. Furthermore, AZD2014, an inhibitor of mTOR, enhanced radiosensitivity and apoptosis in NSCLC cell lines, while mTOR overexpression resulted in radioresistance and cell survival from miR-99a-induced cell apoptosis. Moreover, miR-99a overexpression further increased the efficacy of radiation therapy in an NSCLC xenograft mouse model, and miR-99a and mTOR expression was significantly inversely correlated. Conclusions: Altogether, these data suggested miR-99a functions as a tumor suppressor that has a critical role in regulating radiosensitivity of NSCLC by targeting the mTOR signaling pathway.

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Surfactant Protein B Suppresses Lung Cancer Progression by Inhibiting Secretory Phospholipase A2 Activity and Arachidonic Acid Production

Cited by 31 publications

References 72 publications

Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases that Correlates with Prolonged Survival

Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases that Correlates with Prolonged Survival

Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

MiR-99a Enhances the Radiation Sensitivity of Non-Small Cell Lung Cancer by Targeting mTOR

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