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Elevated Expression of Lumican in Lung Cancer Cells Promotes Bone Metastasis through an Autocrine Regulatory Mechanism.

ABSTRACT: Background: The microarray analysis of whole-genome expression indicated that the gene encoding the protein lumican, which is associated with extracellular matrix (ECM) interaction, was highly expressed in osteotropic lung cancer cell lines with an enhanced capacity of bone metastasis. Methods: The expression of lumican in the osteotropic lung cancer cells was downregulated, and the in vitro migration, invasion, and adhesion of cancer cells to ECM components, and the in vivo bone metastasis capacity of these cells were examined. Exogenous lumican was provided to study the autocrine regulation mechanism of lumican in the bone metastasis of lung cancer cells. Results: Transfection with lumican-specific short hairpin RNA (shRNA) in the osteotropic lung cancer cells reduced the establishment of in vivo bone metastasis, but not lung metastasis. Reduction in the expression of lumican also decreased the attachment of lung osteotropic cancer cells to several components of the ECM and suppressed cell migration and invasion in vitro. Exogenous lumican restored these reduced capacities of lumican knockdown cells and promoted the seeding of lung cancer cells in the bone microenvironment. Conclusions: These results suggested that lumican promotes the metastasis of lung cancer cells to the bones via an autocrine regulatory mechanism, and blocking this interaction may provide a new therapeutic approach to reduce bone metastasis in cases of lung cancer.

SUBMITTER: Hsiao KC

PROVIDER: S-EPMC7016828 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Elevated Expression of Lumican in Lung Cancer Cells Promotes Bone Metastasis through an Autocrine Regulatory Mechanism.

Hsiao Kuan-Chung KC Chu Pei-Yi PY Chang Gee-Chen GC Liu Ko-Jiunn KJ

Cancers 20200117 1

<i>Background</i>: The microarray analysis of whole-genome expression indicated that the gene encoding the protein lumican, which is associated with extracellular matrix (ECM) interaction, was highly expressed in osteotropic lung cancer cell lines with an enhanced capacity of bone metastasis. <i>Methods</i>: The expression of lumican in the osteotropic lung cancer cells was downregulated, and the in vitro migration, invasion, and adhesion of cancer cells to ECM components, and the in vivo bone m ...[more]

PMID: 31963522

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Project description:BackgroundFibroproliferative repair starts early in the inflammatory phase of acute respiratory distress syndrome (ARDS) and indicates a poor prognosis. Lumican, a small leucine-rich proteoglycan, is implicated in homeostasis and fibrogenesis, but its role in ARDS is unclear.MethodsBronchoalveolar lavage fluid (BALF) samples were obtained from ARDS patients (n = 55) enrolled within 24 h of diagnosis and mechanically ventilated (n = 20) and spontaneously breathing (n = 29) control subjects. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse models were intratracheally administered an adeno-associated virus (AAV) vector expressing lumican shRNA. Primary human lung fibroblasts (HLF) and small airway epithelial cells (SAECs) were cultured with tumour necrosis factor (TNF)-α or lumican. Luminex/ELISA, histochemistry/immunohistochemistry, immunofluorescence microscopy, quantitative real-time PCR, and western blotting were performed.ResultsLumican levels were significantly higher in the BALF of ARDS patients than in that of ventilated or spontaneously breathing controls (both p < 0.0001); they were correlated with the PaO2/FiO2 ratio and levels of proinflammatory cytokines (interleukin-6, interleukin-8, and TNF-α) and profibrotic factors (fibronectin, alpha-1 type I collagen [COL1A1], and alpha-1 type III collagen [COL3A1]). Lumican expression was enhanced in the alveolar walls and airway epithelium in the ALI mouse model. Murine lumican levels were also linked to proinflammatory and profibrotic cytokine levels in the BALF. In vitro, TNF-α induced the synthesis and secretion of lumican in HLF. In turn, lumican increased the expression of alpha-smooth muscle actin (α-SMA), COL1A1, and COL3A1 in HLF, upregulated α-SMA and COL3A1, downregulated E-cadherin, and caused spindle-shaped morphological changes in SAECs. Moreover, increased ERK phosphorylation and Slug were noted in both HLF and SAECs treated with lumican. In vivo, AAV-mediated knockdown of lumican inhibited the pulmonary production of fibronectin and COL3A1 and alleviated lung fibrotic lesions in LPS-challenged mice.ConclusionsPulmonary lumican levels were increased early in human and experimental ARDS and linked to disease severity and inflammatory fibrotic processes. Lumican triggers the transdifferentiation of lung fibroblasts into myofibroblasts and epithelial-mesenchymal transition in SAECs, possibly via the ERK/Slug pathway. Knockdown of pulmonary lumican attenuated extracellular matrix deposition in ALI mice. Overall, lumican promotes fibrotic responses in the early phase of ARDS, suggesting its potential as a therapeutic target.

Project description:Objective: Explore the mechanism of CaSR's involvement in bone metastasis in lung adenocarcinoma. Methods: Immunohistochemistry (IHC) was used to detect the expression of calcium-sensing receptor (CaSR) in 120 cases of lung adenocarcinoma with bone metastasis. Stably transfected cell lines with CaSR overexpression and knockdown based on A549 cells were constructed. The expression of CaSR was verified by western blot and qPCR. The proliferation and migration abilities of A549 cells were tested using cholecystokinin-8 (CCK-8) and Transwell assays, respectively. Western blotting was used to detect the expression of matrix metalloproteinases MMP2, MMP9, CaSR, and NF-?B. The supernatant from each cell culture group was collected as a conditional co-culture solution to study the induction of osteoclast precursor cells and osteoblasts. Western blot and qPCR were used to validate the expression of bone matrix degradation-related enzymes cathepsin K and hormone calcitonin receptor (CTR) and osteoblast-induced osteoclast maturation and differentiation enzyme receptor activator of nuclear factor-?B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), osteoprotegerin (OPG), and PTHrP. Immunofluorescent staining was used to detect F-actin ring formation and osteocalcin expression. Western blot results for NF-?B expression identified a regulatory relationship between NF-?B and CaSR. Results: CaSR expression in lung cancer tissues was significantly higher than that in adjacent and normal lung tissues. The expression of CaSR in lung cancer tissues with bone metastasis was higher than that in non-metastatic lung cancer tissues. The proliferation and migration ability of A549 cells increased significantly with overexpressed CaSR. The co-culture solution directly induced osteoclast precursor cells and the expression of bone matrix degradation-related enzymes significantly increased. Osteoblasts were significantly inhibited and osteoblast-induced osteoclast maturation and differentiation enzymes were significantly downregulated. It was found that the expression of NF-?B and PTHrP increased when CaSR was overexpressed. Osteoclast differentiation factor expression was also significantly increased, which directly induces osteoclast differentiation and maturation. These results were reversed when CaSR was knocked down. Conclusions: CaSR can positively regulate NF-?B and PTHrP expression in A549 cells with a high metastatic potential, thereby promoting osteoclast differentiation and maturation, and facilitating the occurrence and development of bone metastasis in lung adenocarcinoma.

Dataset Information

Elevated Expression of Lumican in Lung Cancer Cells Promotes Bone Metastasis through an Autocrine Regulatory Mechanism.

Publications

Elevated Expression of Lumican in Lung Cancer Cells Promotes Bone Metastasis through an Autocrine Regulatory Mechanism.

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