Effects of growth differentiation factor 15 on bone metastasis of lung adenocarcinoma in nude mice by regulating PTEN/PI3K/AKT signaling pathway_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

DUAN Lian ¹ , LI Lina ¹ , ZHOU Jing ¹ , JIAO Mi ¹ , WANG Yuzhen ¹ ,  SUN Wenbo ²

1. The Sixth Department of Internal Medicine, Shaanxi Provincial Cancer Hospital, Xian, Shaanxi 710000, P. R. China;
2. The Third Department of Internal Medicine, Shaanxi Provincial Cancer Hospital, Xian, Shaanxi 710000, P. R. China;

Corresponding author：

SUN Wenbo, Email: xto01q@163.com

Keywords：

Growth differentiation factor 15; phosphatase and tensin homolog/phosphatidylinositol 3 kinase/protein kinase B signaling pathway; lung adenocarcinoma bone metastasis

DOI：

10.7507/1671-6205.202408048

Video：

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Objective To investigate the effects of growth differentiation factor 15 (GDF15) on lung adenocarcinoma bone metastasis in nude mice by regulating phosphatase and tensin homology/phosphatidylinositol 3 kinase/protein kinase B (PTEN/PI3K/AKT) signaling pathway. Methods The bone metastasis model of lung adenocarcinoma in nude mice was established and mice were randomly divided into Control group, sh-NC group, sh-GDF15 group, sh-GDF15+sh-NC group and sh-GDF15+sh-PTEN group. The changes of 50% pain withdrawl threshold (PWT) and thermal withdrawal latency (TWL) were observed. bone destruction was analyzed by Micro-CT. Bone morphology was observed by HE staining. The expression of osteoclast-related factors was detected by immunohistochemistry. The expression of PTEN/PI3K/AKT signaling pathway was detected by Western blot. Results The tibia tissue of nude mice in Control group and sh-NC group was destroyed, the continuity of bone cortex was interrupted, obvious bone tumor lesions were observed, the tumor cells were irregular in shape, densely distributed and disordered, and the nuclei were obviously deformed. Compared with sh-NC group, sh-GDF15 group had less tibial tissue destruction, the bone tumor cell density was significantly reduced, the pathological morphology was significantly improved, and 50% PWT, TWL, bone mineral density (BMD), trabecular bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and PTEN expression were increased, the expressions of trabecular separation (Tb.Sp), cathepsin K (CTSK), matrix metalloproteinase 9 (MMP-9), p-PI3K PI3K and p-Akt/Akt were decreased (P<0.05). Compared with sh-GDF15+sh-NC group, sh-GDF15+sh-PTEN group had severe tibial tissue damage, the bone tissue tumor cells were dense and the pathological injury was aggravated, and 50%PWT, TWL, BMD, BV/TV, Tb.N, Tb.Th and PTEN expression were decreased, the expressions of Tb.Sp, CTSK, MMP-9, p-PI3K /PI3K and p-Akt /Akt were increased (P<0.05). Conclusion GDF15 can promote bone metastasis of lung adenocarcinoma in nude mice, and its mechanism is related to inhibition of PTEN/PI3K/AKT signaling pathway.

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2.	Altorki NK, Markowitz GJ, Gao D, et al. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer, 2019, 19(1): 9-31.
3.	李小梅, 袁文茜, 曹伯旭, 等. 慢性癌症相关性疼痛. 中国疼痛医学杂志, 2021, 27(3): 161-165.
4.	北京医学奖励基金会肺癌青年专家委员会, 中国胸外科肺癌联盟. 肺癌骨转移诊疗专家共识(2019版). 中国肺癌杂志, 2019, 22(4): 187-207.
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6.	Malvi P, Janostiak R, Nagarajan A, et al. Loss of thymidine kinase 1 inhibits lung cancer growth and metastatic attributes by reducing GDF15 expression. PLoS Genet, 2019, 15(10): e1008439-e1008465.
7.	Shi L, Zhu W, Huang Y, et al. Cancer-associated fibroblast-derived exosomal microRNA-20a suppresses the PTEN/PI3K-AKT pathway to promote the progression and chemoresistance of non-small cell lung cancer. Clin Transl Med, 2022, 12(7): e989-e1012.
8.	Liu Y, Lei J, Ji X, et al. Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway. Genes Genomics, 2023, 45(4): 507-517.
9.	孟唤男, 郭晓冬, 周小翠, 等. 骨痛灵方通过抑制整合素αvβ3通路缓解肺癌骨转移癌性疼痛. 中国疼痛医学杂志, 2023, 29(2): 92-100.
10.	杨梦霞, 毛昀, 朱世杰, 等. 骨转移癌痛发生机制的研究进展. 癌变. 畸变. 突变, 2022, 34(4): 324-326.
11.	Deng J, Zhang M, Zhang H, et al. Value of growth/differentiation factor 15 in diagnosis and the evaluation of chemotherapeutic response in lung cancer. Clin Ther, 2021, 43(4): 747-759.
12.	Myojin Y, Hikita H, Sugiyama M, et al. Hepatic stellate cells in hepatocellular carcinoma promote tumor growth via growth differentiation factor 15 production. Gastroenterology, 2021, 160(5): 1741-1754.
13.	艾郁葱, 闫光志. 生长分化因子15沉默抑制人肝癌HepG2增殖及迁移作用研究. 中国实验诊断学, 2023, 27(9): 1088-1091.
14.	He Y, Zhang X, Zhang Y, et al. Growth differentiation factor 15 is required for triple-negative breast cancer cell growth and chemoresistance. Anticancer Drugs, 2023, 34(3): 351-360.
15.	Zhu G, Chen W, Tang CY, et al. Knockout and double knockout of cathepsin K and MMP9 reveals a novel function of cathepsin K as a regulator of osteoclast gene expression and bone homeostasis. Int J Biol Sci, 2022, 18(14): 5522-5538.
16.	Kim Y, Kim J, Lee H, et al. Tetracycline analogs inhibit osteoclast differentiation by suppressing MMP-9-mediated histone H3 cleavage. Int J Mol Sci, 2019, 20(16): 4038-4051.
17.	黄浩然, 凡一诺, 卫杨文祥, 等. 尿石素A介导p38/MAPK通路抑制破骨细胞活性. 中国组织工程研究, 2024, 28(8): 1149-1154.
18.	Chen CY, Chen J, He L, et al. PTEN: Tumor suppressor and metabolic regulator. Front Endocrinol (Lausanne), 2018, 9(1): 338-349.
19.	Xu T, Rao T, Yu WM, et al. Upregulation of NFKBIZ affects bladder cancer progression via the PTEN/PI3K/Akt signaling pathway. Int J Mol Med, 2021, 47(6): 109-120.
20.	Hu M, Zhu S, Xiong S, et al. MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review). Oncol Rep, 2019, 41(3): 1439-1454.
21.	Zhou JS, Yang ZS, Cheng SY, et al. miRNA-425-5p enhances lung cancer growth via the PTEN/PI3K/AKT signaling axis. BMC Pulm Med, 2020, 20(1): 223-229.
22.	Lin Y, Huang Y, Zheng Y, et al. Taurine inhibits lung metastasis in triple-negative breast cancer by modulating macrophage polarization through PTEN-PI3K/Akt/mTOR pathway. J Immunother, 2024, 17(1): 1-4.

1. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin, 2023, 73(1): 17-48.
2. Altorki NK, Markowitz GJ, Gao D, et al. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer, 2019, 19(1): 9-31.
3. 李小梅, 袁文茜, 曹伯旭, 等. 慢性癌症相关性疼痛. 中国疼痛医学杂志, 2021, 27(3): 161-165.
4. 北京医学奖励基金会肺癌青年专家委员会, 中国胸外科肺癌联盟. 肺癌骨转移诊疗专家共识(2019版). 中国肺癌杂志, 2019, 22(4): 187-207.
5. Siddiqui JA, Pothuraju R, Khan P, et al. Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. Cytokine Growth Factor Rev, 2022, 64(1): 71-83.
6. Malvi P, Janostiak R, Nagarajan A, et al. Loss of thymidine kinase 1 inhibits lung cancer growth and metastatic attributes by reducing GDF15 expression. PLoS Genet, 2019, 15(10): e1008439-e1008465.
7. Shi L, Zhu W, Huang Y, et al. Cancer-associated fibroblast-derived exosomal microRNA-20a suppresses the PTEN/PI3K-AKT pathway to promote the progression and chemoresistance of non-small cell lung cancer. Clin Transl Med, 2022, 12(7): e989-e1012.
8. Liu Y, Lei J, Ji X, et al. Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway. Genes Genomics, 2023, 45(4): 507-517.
9. 孟唤男, 郭晓冬, 周小翠, 等. 骨痛灵方通过抑制整合素αvβ3通路缓解肺癌骨转移癌性疼痛. 中国疼痛医学杂志, 2023, 29(2): 92-100.
10. 杨梦霞, 毛昀, 朱世杰, 等. 骨转移癌痛发生机制的研究进展. 癌变. 畸变. 突变, 2022, 34(4): 324-326.
11. Deng J, Zhang M, Zhang H, et al. Value of growth/differentiation factor 15 in diagnosis and the evaluation of chemotherapeutic response in lung cancer. Clin Ther, 2021, 43(4): 747-759.
12. Myojin Y, Hikita H, Sugiyama M, et al. Hepatic stellate cells in hepatocellular carcinoma promote tumor growth via growth differentiation factor 15 production. Gastroenterology, 2021, 160(5): 1741-1754.
13. 艾郁葱, 闫光志. 生长分化因子15沉默抑制人肝癌HepG2增殖及迁移作用研究. 中国实验诊断学, 2023, 27(9): 1088-1091.
14. He Y, Zhang X, Zhang Y, et al. Growth differentiation factor 15 is required for triple-negative breast cancer cell growth and chemoresistance. Anticancer Drugs, 2023, 34(3): 351-360.
15. Zhu G, Chen W, Tang CY, et al. Knockout and double knockout of cathepsin K and MMP9 reveals a novel function of cathepsin K as a regulator of osteoclast gene expression and bone homeostasis. Int J Biol Sci, 2022, 18(14): 5522-5538.
16. Kim Y, Kim J, Lee H, et al. Tetracycline analogs inhibit osteoclast differentiation by suppressing MMP-9-mediated histone H3 cleavage. Int J Mol Sci, 2019, 20(16): 4038-4051.
17. 黄浩然, 凡一诺, 卫杨文祥, 等. 尿石素A介导p38/MAPK通路抑制破骨细胞活性. 中国组织工程研究, 2024, 28(8): 1149-1154.
18. Chen CY, Chen J, He L, et al. PTEN: Tumor suppressor and metabolic regulator. Front Endocrinol (Lausanne), 2018, 9(1): 338-349.
19. Xu T, Rao T, Yu WM, et al. Upregulation of NFKBIZ affects bladder cancer progression via the PTEN/PI3K/Akt signaling pathway. Int J Mol Med, 2021, 47(6): 109-120.
20. Hu M, Zhu S, Xiong S, et al. MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review). Oncol Rep, 2019, 41(3): 1439-1454.
21. Zhou JS, Yang ZS, Cheng SY, et al. miRNA-425-5p enhances lung cancer growth via the PTEN/PI3K/AKT signaling axis. BMC Pulm Med, 2020, 20(1): 223-229.
22. Lin Y, Huang Y, Zheng Y, et al. Taurine inhibits lung metastasis in triple-negative breast cancer by modulating macrophage polarization through PTEN-PI3K/Akt/mTOR pathway. J Immunother, 2024, 17(1): 1-4.

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Latest ArticlesEffects of growth differentiation factor 15 on bone metastasis of lung adenocarcinoma in nude mice by regulating PTEN/PI3K/AKT signaling pathway

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