BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

Huang, Fei; Yun, Cao; Wu, Gui; Chen, Junying; CaihongWang,; Lin, Wanzun; Lan, Ruilong; Wu, Bing; Xie, Xianhe; Hong, Jinsheng

doi:10.1111/jcmm.15702

Cited by 31 publications

(31 citation statements)

References 79 publications

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“…Lee et al (2016) has demonstrated that PNMA5 is highly expressed in colon cancer and can enhance the apoptosis of breast cancer cells in vitro. According to our RNA-seq data in the previous report (Huang et al, 2020), the expression of Pnma5 is found to be higher in bone metastatic tumors of Lewis lung carcinoma than in lung metastatic tumors and parental Lewis lung cells. However, researches on the roles that PNMA5 play in NSCLC are rare.…”

Section: Introductionsupporting

confidence: 54%

“…High expression of BMP2 in the stroma may result in poor prognosis in NSCLC (Rajski et al, 2015). In our previous reports, BMP2 signaling is found to enhance NSCLC bone metastases via both osteolytic and osteoblastic mechanisms (Huang et al, 2020). However, the downstream target genes of BMP2 signaling associated with NSCLC bone metastases still remain unknown.…”

Section: Introductionmentioning

confidence: 95%

“…Bone metastatic tumor sizes were measured by tumor length and width by using clipper directly and lung metastatic tumor sizes were measured via the HE staining photos. The tumor volumes were calculated via the formula V = (L × W × W)/2, where V is tumor volume, W is tumor width, L is tumor length (Huang et al, 2020).…”

Section: Lewis Lung Carcinoma Metastasismentioning

confidence: 99%

“…The tissue sections were treated as what mentioned in the previous report (Huang et al, 2020). The sections were cut into 2.5 µm tissue sections after they were embedded in paraffin.…”

Section: Hematoxylin and Eosin Stainmentioning

confidence: 99%

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PNMA5 Promotes Bone Metastasis of Non-small-Cell Lung Cancer as a Target of BMP2 Signaling

Huang

Yun

Wang

et al. 2021

Front. Cell Dev. Biol.

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Bone metastases frequently occur in NSCLC patients at the late stage, indicating poor survival. However, mechanisms about the initiation of NSCLC bone metastases remain largely unclear. In our previous reports, BMP2 signaling activation has been found to enhance NSCLC bone metastases through enhancing carcinoma cells migration, invasion, osteoclasts differentiation and osteoblasts immature differentiation. Nevertheless, downstream target genes of BMP2 contributing to those processes still remain unknown. In this project, we find that the expression of Pnma5 is higher in metastatic bone tumors of Lewis lung carcinoma than in metastatic lung tumors and parental Lewis lung cells. Pnma5 overexpression not only can promote cell migration and invasion of NSCLC cells but also tumor-induced osteoclasts differentiation. Interestingly, knockdown of Pnma5 in Lewis lung cells blocks BMP2 signaling from inducing Lewis lung cells migration and invasion. Although BMP2 signaling can promote Lewis lung cells-induced osteoclasts differentiation from macrophages, this effect can also be blocked when Pnma5 is knocked down in Lewis lung cells. Moreover, Pnma5 can promote NSCLC bone metastases in vivo as the downstream target of BMP2. Those results above indicate that BMP2 signaling enhances NSCLC bone metastases via its direct downstream target gene Pnma5. This research reveals the detailed molecular mechanism about how BMP2 signaling contributes to NSCLC bone metastases via PNMA5 and provides a new potential therapeutic target for the treatment of NSCLC bone metastases.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 95%

Section: Lewis Lung Carcinoma Metastasismentioning

confidence: 99%

“…The tissue sections were treated as what mentioned in the previous report (Huang et al, 2020). The sections were cut into 2.5 µm tissue sections after they were embedded in paraffin.…”

Section: Hematoxylin and Eosin Stainmentioning

confidence: 99%

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PNMA5 Promotes Bone Metastasis of Non-small-Cell Lung Cancer as a Target of BMP2 Signaling

Huang

Yun

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…The high expression of BMP2 in primary lung fibroblasts could predict a poor prognosis of LUAD patients [ 24 ]. BMP2 silencing inhibited the proliferation and migration of lung cancer cells [ 25 ], and BMP2 signaling activation promoted bone metastases and invasion in NSCLC [ 26 ]. There was no difference in the expression of BMP4 in LUAD tissue compared with normal lung tissue but it was associated with the ethnicity and prognosis of LUAD in the present study.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Expression and Prognostic Significance of Bone Morphogenetic Proteins and Their Receptors in Lung Adenocarcinoma

Chen

2021

BioMed Research International

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Background. Lung adenocarcinoma (LUAD) is one of the most life-threatening malignancies. The crucial role of bone morphogenetic protein (BMP)/BMP receptors reveals the significance of exploring BMP protein-related prognostic predictors in LUAD. Methods. The mRNA expression of BMPs/BMP receptors was investigated in LUAD and normal lung tissues. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed, and the prognostic values were assessed by Kaplan-Meier Plotter. Univariate and multivariate Cox regression analyses were executed to ascertain the correlation between overall survival (OS) and the mRNA expression of BMPs/BMP receptors. The receiver operating characteristic (ROC) curves were implemented to evaluate the predictive power of the prognostic model. Then, the prognostic model was validated in the GEO cohort. Furthermore, a nomogram comprising the prognostic model was established. Results. The mRNA expression of BMP2/5/6/R2, ACVRL1, and TGFBR2/3 was lower in LUAD tissues than in normal lung tissues. High expression of BMP2/4/5/R1A/R2, ACVR1/2A/L1, and TGFBR1/3 was associated with better OS, while BMP7 and ACVR1C/2B were associated with poorer OS. Three genes (BMP5, BMP7, and ACVR2A) were screened by univariate and multivariate Cox regression analyses to develop the prognostic model in TCGA. Significantly better survival was observed in LUAD patients with a low-risk score than those with a high-risk score. The ROC curves confirmed the good performance of the prognostic model, then, the prognostic model was validated in the GSE31210 dataset. A nomogram was constructed (AUCs>0.7). And hub genes were further evaluated, including gene set enrichment analysis and immune cell infiltration. Conclusions. BMP5, BMP7, and ACVR2A are potential therapeutic targets in LUAD. The three-gene prognostic model and the nomogram are reliable tools for predicting the OS of LUAD patients.

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RGMb impacts partial epithelial‐mesenchymal transition and BMP2‐Induced ID mRNA expression independent of PD‐L2 in nonsmall cell lung cancer cells

Dorset,

Daugaard,

Larsen

et al. 2023

Cell Biology International

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PD‐1/PD‐ligand‐axis immunotherapy‐mediated activation of T‐cells for cancer cell elimination is a promising treatment of nonsmall cell lung cancer (NSCLC). However, the effect of immunotherapy on intracellular signaling pathways in cancer cells still needs further delineation. Repulsive Guidance Molecule b (RGMb), a regulator of Bone Morphogenetic Proteins (BMPs) signaling, interacts with the PD‐ligand, PD‐L2, at cancer cell membranes. Accordingly, a clarification of the functions of RGMb and its relation to PD‐L2 might provide insight into NSCLC cell signaling responses to PD‐1/PD‐ligand‐axis immunotherapy. In this study, the functions of RGMb and PD‐L2 were examined using the two NSCLC cell lines HCC827 and A549. CRISPR/Cas9 was used to decrease the expression of RGMb and PD‐L2, while lentiviral vectors were used to increase their expression. Downstream effects were examined by RT‐qPCR and immunoassays. Ectopic expression of RGMb impacted BMP2‐induced expression of ID1 and ID2 messenger RNA (mRNA) independently of PD‐L2, while RGMb depletion by CRISPR/Cas9 did not affect the BMP2‐mediated induction of ID1, ID2, and ID3 mRNA. However, depletion of RGMb resulted in a partial epithelial‐mesenchymal transition (EMT) gene expression profile in HCC827 cells, which was not mimicked by PD‐L2 depletion. The results show that RGMb is a coregulator of BMP signaling and hence, ID mRNA expression and that RGMb can control the EMT balance in NSCLC cells. However, RGMb appears to exert these functions independently of PD‐L2, and accordingly, the PD‐1/PD‐ligand axis for immune surveillance in NSCLC cells.

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BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

Cited by 31 publications

References 79 publications

PNMA5 Promotes Bone Metastasis of Non-small-Cell Lung Cancer as a Target of BMP2 Signaling

PNMA5 Promotes Bone Metastasis of Non-small-Cell Lung Cancer as a Target of BMP2 Signaling

Abnormal Expression and Prognostic Significance of Bone Morphogenetic Proteins and Their Receptors in Lung Adenocarcinoma

RGMb impacts partial epithelial‐mesenchymal transition and BMP2‐Induced ID mRNA expression independent of PD‐L2 in nonsmall cell lung cancer cells

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