Serum microRNA-139-5p is downregulated in lung cancer patients with lytic bone metastasis

Xu,Song; Yang,Fan; Liu,Renwang; Li,Xiongfei; Fan,Haiyang; Liu,Jinghao; Wei,Sen; Chen,Gang; Chen,Jun; Da,Yurong

doi:10.3892/or.2018.6316

Serum microRNA-139-5p is downregulated in lung cancer patients with lytic bone metastasis

Authors:
- Song Xu
- Fan Yang
- Renwang Liu
- Xiongfei Li
- Haiyang Fan
- Jinghao Liu
- Sen Wei
- Gang Chen
- Jun Chen
- Yurong Da
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Affiliations: Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China, Department of Immunology, School of Basic Medical Sciences, Research Center of Basic Medical Science, Tianjin Key Laboratory of Cellular and Molecular Immunology and Key Laboratory of The Educational Ministry of China, Tianjin Medical University, Tianjin 300070, P.R. China
Published online on: March 15, 2018 https://doi.org/10.3892/or.2018.6316
Pages: 2376-2384

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Abstract

Bone remodeling can be interrupted by tumor cells which leads to an inappropriate balance of osteoblasts and osteoclasts. As the progenitors of osteoblasts, mesenchymal stem cells (MSCs) have been reported to exhibit an abnormal osteogenic differentiation potential in some cancer‑related bone lesions. However, the evidence is very limited in terms of the biological alterations of MSCs in the bone metastasis of non‑small cell lung cancers (NSCLC). We investigated the expression and function of miR‑139‑5p in MSC osteogenic differentiation in vitro in normal and NSCLC-exposed condition. Then, we compared the serum miR‑139‑5p in stage IV lung adenocarcinoma cancer patients with and without lytic bone metastasis. We found that MSCs exhibited a significant increase in miR‑139‑5p expression after exposure to osteogenic differentiation induction medium. However, Notch1, which was confirmed as a target of miR‑139‑5p by luciferase and western blot assays, showed a marked downregulated expression together with its pathway downstream factors during MSC osteogenesis. miR‑139‑5p positively regulated MSC osteogenic differentiation but this effect was abrogated significantly by Notch1 knockdown. After exposure to conditions of lung cancer cells A549 and L9981, MSCs exhibited significant downregulation of miR‑139‑5p expression and early osteogenic marker ALP activity. Furthermore, we demonstrated that the expression of serum miR‑139‑5p from lung adenocarcinoma patients with lytic bone metastasis was significantly lower compared to that in patients with metastases in other organs. The potential roles of miR‑139‑5p as a biomarker and treatment target in monitoring and controlling bone metastasis in lung cancer patients are worthy of being further explored.

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1	Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 12:6243s–6249s. 2006. View Article : Google Scholar : PubMed/NCBI
2	Liu R, Wei S, Chen J and Xu S: Mesenchymal stem cells in lung cancer tumor microenvironment: Their biological properties, influence on tumor growth and therapeutic implications. Cancer Lett. 353:145–152. 2014. View Article : Google Scholar : PubMed/NCBI
3	Zhang L, Dong Y, Zhu N, Tsoi H, Zhao Z, Wu CW, Wang K, Zheng S, Ng SS, Chan FK, et al: microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer. Mol Cancer. 13:1242014. View Article : Google Scholar : PubMed/NCBI
4	Xu W, Hang M, Yuan CY, Wu FL, Chen SB and Xue K: MicroRNA-139-5p inhibits cell proliferation and invasion by targeting insulin-like growth factor 1 receptor in human non-small cell lung cancer. Int J Clin Exp Pathol. 8:3864–3870. 2015.PubMed/NCBI
5	Dai S, Wang X, Li X and Cao Y: MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme. Biochem Biophys Res Commun. 467:204–210. 2015. View Article : Google Scholar : PubMed/NCBI
6	Yonemori M, Seki N, Yoshino H, Matsushita R, Miyamoto K, Nakagawa M and Enokida H: Dual tumor-suppressors miR-139-5p and miR-139-3p targeting matrix metalloprotease 11 in bladder cancer. Cancer Sci. 107:1233–1242. 2016. View Article : Google Scholar : PubMed/NCBI
7	Dai H, Gallagher D, Schmitt S, Pessetto ZY, Fan F, Godwin AK and Tawfik O: Role of miR-139 as a surrogate marker for tumor aggression in breast cancer. Hum Pathol. 61:68–77. 2017. View Article : Google Scholar : PubMed/NCBI
8	Xu S, Santini Cecilia G, De Veirman K, Vande Broek I, Leleu X, De Becker A, Van Camp B, Vanderkerken K and Van Riet I: Upregulation of miR-135b is involved in the impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients. PLoS One. 8:e797522013. View Article : Google Scholar : PubMed/NCBI
9	Menu E, Kooijman R, Van Valckenborgh E, Asosingh K, Bakkus M, Van Camp B and Vanderkerken K: Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: Study in the 5T33MM model. Br J Cancer. 90:1076–1083. 2004. View Article : Google Scholar : PubMed/NCBI
10	Xu S, Menu E, De Becker A, Van Camp B, Vanderkerken K and Van Riet I: Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favor myeloma cell growth in vitro and in vivo. Stem Cells. 30:266–279. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zanotti S, Smerdel-Ramoya A, Stadmeyer L, Durant D, Radtke F and Canalis E: Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology. 149:3890–3899. 2008. View Article : Google Scholar : PubMed/NCBI
12	Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg HM, Teitelbaum SL, Ross FP, Kopan R and Long F: Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 14:306–314. 2008. View Article : Google Scholar : PubMed/NCBI
13	Xu S, Evans H, Buckle C, De Veirman K, Hu J, Xu D, Menu E, De Becker A, Vande Broek I, Leleu X, et al: Impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients is associated with a blockade in the deactivation of the Notch signaling pathway. Leukemia. 26:2546–2549. 2012. View Article : Google Scholar : PubMed/NCBI
14	Gunn WG, Conley A, Deininger L, Olson SD, Prockop DJ and Gregory CA: A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: A potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells. 24:986–991. 2006. View Article : Google Scholar : PubMed/NCBI
15	Yu PF, Huang Y, Xu CL, Lin LY, Han YY, Sun WH, Hu GH, Rabson AB, Wang Y and Shi YF: Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis. Oncogene. 36:840–849. 2017. View Article : Google Scholar : PubMed/NCBI
16	Li M, Wu Y, Liu R, Guo L, Xu T, Chen J and Xu S: Investigational study of mesenchymal stem cells on lung cancer cell proliferation and invasion. Zhongguo Fei Ai Za Zhi. 18:674–679. 2015.(In Chinese). PubMed/NCBI
17	Roato I: Bone metastases: When and how lung cancer interacts with bone. World J Clin Oncol. 5:149–155. 2014. View Article : Google Scholar : PubMed/NCBI