瘦素上调GRP78的表达在肺癌细胞迁移中的作用

吴优其乐; 蔺晓菁; 吴晶晶; 练雪梅

doi:10.16016/j.1000-5404.201911165

您当前的位置：

首页 >

文章列表页 >

瘦素上调GRP78的表达在肺癌细胞迁移中的作用

基础医学 | 更新时间：2026-01-09

- 瘦素上调GRP78的表达在肺癌细胞迁移中的作用
- Role of leptin up-regulated GRP78 expression in migration of lung cancer cells
- 第三军医大学学报 2020年42卷第8期页码：799-806
- 作者机构：
- 作者简介：
- 基金信息：
  
  国家自然科学基金面上项目(81973030);重庆市技术创新与应用发展专项(CSTC2019jscx-msxmX0280)
- DOI：10.16016/j.1000-5404.201911165
  中图分类号：
- 收稿：2019-11-20，
  
  纸质出版：2020-04-30
- 稿件说明：
移动端阅览
吴优其乐, 蔺晓菁, 吴晶晶, 等. 瘦素上调GRP78的表达在肺癌细胞迁移中的作用[J]. 第三军医大学学报, 2020,42(8):799-806.

Youqile WU, Xiaojing LIN, Jingjing WU, et al. Role of leptin up-regulated GRP78 expression in migration of lung cancer cells[J]. Journal of Third Military Medical University, 2020, 42(8): 799-806.
吴优其乐, 蔺晓菁, 吴晶晶, 等. 瘦素上调GRP78的表达在肺癌细胞迁移中的作用[J]. 第三军医大学学报, 2020,42(8):799-806. DOI： 10.16016/j.1000-5404.201911165.

Youqile WU, Xiaojing LIN, Jingjing WU, et al. Role of leptin up-regulated GRP78 expression in migration of lung cancer cells[J]. Journal of Third Military Medical University, 2020, 42(8): 799-806. DOI： 10.16016/j.1000-5404.201911165.

摘要

Abstract

Objective

To investigate the effect of leptin on the migration of lung cancer cell lines A549 and H460 and the potential mechanisms.

Methods

The GEPIA website was used to analyze the correlation of the expression levels of leptin and glucose-regulated protein-78 (GRP78) with overall survival rate in lung cancer patients from TCGA database. Wound healing assay was used to detect the effect of leptin and HA15 (GRP78 targeting inhibitor) on the migration of lung cancer A549 and H460 cells; Immunofluorescence assay was used to measure the expression of GRP78 in lung cancer cells. Finally

lung cancer A549 cells were treated with PI3K targeting inhibitor Ly294002

mTOR targeting inhibitor rapamycin alone or in combination with leptin

and then Western blot assay was used to investigate the impact of leptin on PI3K/mTOR/STAT3 signaling pathway and GRP78 expression.

Results

Survival analysis showed that high expression of leptin or GRP78 was closely related to decreased overall survival rate in lung cancer patients (

0.05). Wound healing test indicated that leptin enhanced the migration of lung cancer A549 and H460 cells (

0.05). Immunofluorescence assay displayed that leptin upregulated GRP78 expression in A549 and H460 cells (

0.01). Western blot assay suggested that leptin could upregulate the expression of GRP78 in lung cancer A549 cells through PI3K/mTOR/STAT3 signaling pathway (

0.001). Wound healing test showed inhibition of GRP78 attenuated the effect of leptin on promoting migration.

Conclusion

Leptin promotes the migration of lung cancer cells by up-regulating GRP78 through PI3K/mTOR/STAT3 signaling pathway.

关键词

Keywords

references

BRAY F FERLAY J SOERJOMATARAM I Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 6 394 424 10.3322/caac.21492 https://www.ncbi.nlm.nih.gov/pubmed/30207593/ BRAY F, FERLAY J, SOERJOMATARAM I, et al . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J ] . CA Cancer J Clin, 2018, 68(6): 394-424. DOI:10.3322/caac.21492.

CHEN W SUN K ZHENG R Cancer incidence and mortality in China, 2014 Chin J Cancer Res 2018 30 1 1 12 10.21147/j.issn.1000-9604.2018.01.01 https://www.ncbi.nlm.nih.gov/pubmed/29545714 CHEN W, SUN K, ZHENG R, et al . Cancer incidence and mortality in China, 2014 [J ] . Chin J Cancer Res, 2018, 30(1):1-12. DOI:10.21147/j.issn.1000-9604.2018.01.01.

OZRETIC' L HEUKAMP L C ODENTHAL M The role of molecular diagnostics in cancer diagnosis and treatment Onkologie 2012 35 s1 8 12 10.1159/000334823 10.1159/000334823 http://cn.bing.com/academic/profile?id=ea4106869ecc6ac6e3a57cd6886bf5cb&encoded=0&v=paper_preview&mkt=zh-cn OZRETIC' L, HEUKAMP L C, ODENTHAL M, et al . The role of molecular diagnostics in cancer diagnosis and treatment[J ] . Onkologie, 2012, 35(s1): 8-12. DOI: 10.1159/000334823.

SCHABATH M B NGUYEN A WILSON P Temporal trends from 1986 to 2008 in overall survival of small cell lung cancer patients Lung Cancer 2014 86 1 14 21 10.1016/j.lungcan.2014.07.014 SCHABATH M B, NGUYEN A, WILSON P, et al . Temporal trends from 1986 to 2008 in overall survival of small cell lung cancer patients[J ] . Lung Cancer, 2014, 86(1): 14-21. DOI:10.1016/j.lungcan.2014.07.014.

URAMOTO H TANAKA F Recurrence after surgery in patients with NSCLC Transl Lung Cancer Res 2014 3 4 242 249 10.3978/j.issn.2218-6751.2013.12.05 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367696/ URAMOTO H, TANAKA F. Recurrence after surgery in patients with NSCLC[J]. Transl Lung Cancer Res, 2014, 3(4): 242-249. DOI: 10.3978/j.issn.2218-6751.2013.12.05.

HANAHAN D WEINBERG R A Hallmarks of cancer: the next generation Cell 2011 144 5 646 674 10.1016/j.cell.2011.02.013 10.1016/j.cell.2011.02.013 http://cn.bing.com/academic/profile?id=df3bd45ee88e73ce864e969a2ecca2fb&encoded=0&v=paper_preview&mkt=zh-cn HANAHAN D, WEINBERG R A. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-674. DOI: 10.1016/j.cell.2011.02.013.

RAY A CLEARY M P The potential role of leptin in tumor invasion and metastasis Cytokine Growth Factor Rev 2017 38 80 97 10.1016/j.cytogfr.2017.11.002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720178/ RAY A, CLEARY M P. The potential role of leptin in tumor invasion and metastasis[J]. Cytokine Growth Factor Rev, 2017, 38: 80-97. DOI: 10.1016/j.cytogfr.2017.11.002.

VANSAUN M N Molecular pathways: adiponectin and leptin signaling in cancer Clin Cancer Res 2013 19 8 1926 1932 10.1158/1078-0432.CCR-12-0930 http://cn.bing.com/academic/profile?id=fcb23af04a6c856aae4956a0e941bfe8&encoded=0&v=paper_preview&mkt=zh-cn VANSAUN M N. Molecular pathways: adiponectin and leptin signaling in cancer[J]. Clin Cancer Res, 2013, 19(8): 1926-1932. DOI:10.1158/1078-0432.CCR-12-0930.

ZHENG X J YANG Z X DONG Y J Downregulation of leptin inhibits growth and induces apoptosis of lung cancer cellsvia the Notch and JAK/STAT3 signaling pathways Biol Open 2016 5 6 794 800 10.1242/bio.017798 https://bio.biologists.org/content/biolopen/early/2016/05/11/bio.017798.full.pdf ZHENG X J, YANG Z X, DONG Y J, et al . Downregulation of leptin inhibits growth and induces apoptosis of lung cancer cellsvia the Notch and JAK/STAT3 signaling pathways[J ] . Biol Open, 2016, 5(6): 794-800. DOI:10.1242/bio.017798.

BROCCHIERI L CONWAY DE MACARIO E MACARIO A J Hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions BMC Evol Biol 2008 8 19 10.1186/1471-2148-8-19 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2266713/ BROCCHIERI L, CONWAY DE MACARIO E, MACARIO A J. Hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions[J]. BMC Evol Biol, 2008, 8: 19. DOI: 10.1186/1471-2148-8-19.

SUN Q HUA J WANG Q Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer Mol Biol Rep 2012 39 6 6753 6761 10.1007/s11033-012-1500-8 SUN Q, HUA J, WANG Q, et al . Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer[J ] . Mol Biol Rep, 2012, 39(6): 6753-6761. DOI: 10.1007/s11033-012-1500-8.

LEE A S GRP78 induction in cancer: therapeutic and prognostic implications Cancer Res 2007 67 8 3496 3499 10.1158/0008-5472.CAN-07-0325 LEE A S. GRP78 induction in cancer: therapeutic and prognostic implications[J]. Cancer Res, 2007, 67(8): 3496-3499. DOI: 10.1158/0008-5472.CAN-07-0325.

MA X GUO W YANG S Serum GRP78 as a tumor marker and its prognostic significance in non-small cell lung cancers: a retrospective study Dis Markers 2015 2015 814670 10.1155/2015/814670 MA X, GUO W, YANG S, et al . Serum GRP78 as a tumor marker and its prognostic significance in non-small cell lung cancers: a retrospective study[J ] . Dis Markers, 2015, 2015: 814670. DOI: 10.1155/2015/814670.

KWON D KOH J KIM S Overexpression of endoplasmic reticulum stress-related proteins, XBP1s and GRP78, predicts poor prognosis in pulmonary adenocarcinoma Lung Cancer 2018 122 131 137 10.1016/j.lungcan.2018.06.005 KWON D, KOH J, KIM S, et al . Overexpression of endoplasmic reticulum stress-related proteins, XBP1s and GRP78, predicts poor prognosis in pulmonary adenocarcinoma[J ] . Lung Cancer, 2018, 122: 131-137. DOI: 10.1016/j.lungcan.2018.06.005.

THON M HOSOI T YOSHII M Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells Sci Rep 2014 4 7096 10.1038/srep07096 THON M, HOSOI T, YOSHII M, et al . Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells[J ] . Sci Rep, 2014, 4: 7096. DOI: 10.1038/srep07096.

HUANG Y X JIN Q N SU M Leptin promotes the migration and invasion of breast cancer cells by upregulating ACAT2 Cell Oncol (Dordr) 2017 40 6 537 547 10.1007/s13402-017-0342-8 HUANG Y X, JIN Q N, SU M, et al . Leptin promotes the migration and invasion of breast cancer cells by upregulating ACAT2[J ] . Cell Oncol (Dordr), 2017, 40(6): 537-547. DOI: 10.1007/s13402-017-0342-8.

AL-SHIBLI S M HARUN N ASHOUR A E Expression of leptin and leptin receptors in colorectal cancer-an immunohistochemical study Peer J 2019 7 e7624 10.7717/peerj.7624 AL-SHIBLI S M, HARUN N, ASHOUR A E, et al . Expression of leptin and leptin receptors in colorectal cancer-an immunohistochemical study[J ] . Peer J, 2019, 7: e7624. DOI: 10.7717/peerj.7624.

TONG X MA Y ZHOU Q L Serum and tissue leptin in lung cancer: a meta-analysis Oncotarget 2017 8 12 19699 19711 10.18632/oncotarget.14963 TONG X, MA Y, ZHOU Q L, et al . Serum and tissue leptin in lung cancer: a meta-analysis[J ] . Oncotarget, 2017, 8(12): 19699-19711. DOI: 10.18632/oncotarget.14963.

HOUSA D HOUSOVA J VERNEROVA Z Adipocytokines and cancer Physiol Res 2006 55 3 233 244 10.1016/j.bioeng.2004.09.001 HOUSA D, HOUSOVA J, VERNEROVA Z, et al . Adipocytokines and cancer[J ] . Physiol Res, 2006, 55(3):233-244. DOI: 10.1016/j.bioeng.2004.09.001.

AMBROSINI G NATH A K SIERRA-HONIGMANN M R Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1 J Biol Chem 2002 277 37 34601 34609 10.1074/jbc.M205172200 AMBROSINI G, NATH A K, SIERRA-HONIGMANN M R, et al . Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1[J ] . J Biol Chem, 2002, 277(37): 34601-34609. DOI: 10.1074/jbc.M205172200.

SONG C H LIAO J DENG Z H Is leptin a predictive factor in patients with lung cancer? Clin Biochem 2014 47 3 230 232 10.1016/j.clinbiochem.2013.12.003 SONG C H, LIAO J, DENG Z H, et al . Is leptin a predictive factor in patients with lung cancer?[J ] . Clin Biochem, 2014, 47(3): 230-232. DOI: 10.1016/j.clinbiochem.2013.12.003.

ANAR C DENIZ D EROL S Are serum leptin levels a prognostic factor in advanced lung cancer? Bratisl Lek Listy 2017 118 1 13 16 10.4149/BLL_2017_003 ANAR C, DENIZ D, EROL S, et al . Are serum leptin levels a prognostic factor in advanced lung cancer?[J ] . Bratisl Lek Listy, 2017, 118(1): 13-16. DOI: 10.4149/BLL_2017_003.

HEBERT-SCHUSTER M ROTTA B E KIRKPATRICK B The interplay between glucose-regulated protein 78 (GRP78) and steroids in the reproductive system Int J Mol Sci 2018 19 7 E1842 10.3390/ijms19071842 HEBERT-SCHUSTER M, ROTTA B E, KIRKPATRICK B, et al . The interplay between glucose-regulated protein 78 (GRP78) and steroids in the reproductive system[J ] . Int J Mol Sci, 2018, 19(7): E1842. DOI: 10.3390/ijms19071842.

CASAS C GRP78 at the centre of the stage in cancer and neuroprotection Front Neurosci 2017 11 177 10.3389/fnins.2017.00177 CASAS C. GRP78 at the centre of the stage in cancer and neuroprotection[J]. Front Neurosci, 2017, 11: 177. DOI: 10.3389/fnins.2017.00177.

HUANG Y Y PU L J SONG L L Knockdown of GRP78 enhances cell death by cisplatin and radiotherapy in nasopharyngeal cells Anticancer Drugs 2016 27 8 726 733 10.1097/CAD.0000000000000377 HUANG Y Y, PU L J, SONG L L, et al . Knockdown of GRP78 enhances cell death by cisplatin and radiotherapy in nasopharyngeal cells[J ] . Anticancer Drugs, 2016, 27(8): 726-733. DOI: 10.1097/CAD.0000000000000377.

DAUER P SHARMA N S GUPTA V K GRP78-mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells Mol Oncol 2018 12 9 1498 1512 10.1002/1878-0261.12322 https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1878-0261.12322 DAUER P, SHARMA N S, GUPTA V K, et al . GRP78-mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells[J ] . Mol Oncol, 2018, 12(9): 1498-1512. DOI: 10.1002/1878-0261.12322.

COOK K L CLARKE R Role of GRP78 in promoting therapeutic-resistant breast cancer Future Med Chem 2015 7 12 1529 1534 10.4155/FMC.15.80 http://cn.bing.com/academic/profile?id=70dbce9e33ed10a92d49eccb1ac3288d&encoded=0&v=paper_preview&mkt=zh-cn COOK K L, CLARKE R. Role of GRP78 in promoting therapeutic-resistant breast cancer[J]. Future Med Chem, 2015, 7(12): 1529-1534. DOI: 10.4155/FMC.15.80.

ISHIKAWA D TAKEUCHI S NAKAGAWA T mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF PLoS ONE 2013 8 5 e62104 10.1371/journal.pone.0062104 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653905/ ISHIKAWA D, TAKEUCHI S, NAKAGAWA T, et al . mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF[J ] . PLoS ONE, 2013, 8(5): e62104. DOI: 10.1371/journal.pone.0062104.

FUMAROLA C BONELLI M A PETRONINI P G Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer Biochem Pharmacol 2014 90 3 197 207 10.1016/j.bcp.2014.05.011 http://cn.bing.com/academic/profile?id=badf4139d9f522a20d9b5561ff022382&encoded=0&v=paper_preview&mkt=zh-cn FUMAROLA C, BONELLI M A, PETRONINI P G, et al . Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer[J ] . Biochem Pharmacol, 2014, 90(3): 197-207. DOI: 10.1016/j.bcp.2014.05.011.

YU H LEE H HERRMANN A Revisiting STAT3 signalling in cancer: new and unexpected biological functions Nat Rev Cancer 2014 14 11 736 746 10.1038/nrc3818 https://www.ncbi.nlm.nih.gov/pubmed/25342631 YU H, LEE H, HERRMANN A, et al . Revisiting STAT3 signalling in cancer: new and unexpected biological functions[J ] . Nat Rev Cancer, 2014, 14(11): 736-746. DOI: 10.1038/nrc3818.

GRABNER B SCHRAMEK D MUELLER K M Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis Nat Commun 2015 6 6285 10.1038/ncomms7285 http://cn.bing.com/academic/profile?id=622461896c0dff0048a1e7b1b2f392ee&encoded=0&v=paper_preview&mkt=zh-cn GRABNER B, SCHRAMEK D, MUELLER K M, et al . Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis[J ] . Nat Commun, 2015, 6: 6285. DOI: 10.1038/ncomms7285.

ZHOU J J QU Z X YAN S P Differential roles of STAT3 in the initiation and growth of lung cancer Oncogene 2015 34 29 3804 3814 10.1038/onc.2014.318 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387125/ ZHOU J J, QU Z X, YAN S P, et al . Differential roles of STAT3 in the initiation and growth of lung cancer[J ] . Oncogene, 2015, 34(29): 3804-3814. DOI: 10.1038/onc.2014.318.

CHEN J Multiple signal pathways in obesity-associated cancer Obes Rev 2011 12 12 1063 1070 10.1111/j.1467-789X.2011.00917.x CHEN J. Multiple signal pathways in obesity-associated cancer[J]. Obes Rev, 2011, 12(12): 1063-1070. DOI: 10.1111/j.1467-789X.2011.00917.x.

JAFFE T SCHWARTZ B Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal-transduction pathways Int J Cancer 2008 123 11 2543 2556 10.1002/ijc.23821 https://www.academia.edu/25601470/Leptin_promotes_motility_and_invasiveness_in_human_colon_cancer_cells_by_activating_multiple_signal-transduction_pathways JAFFE T, SCHWARTZ B. Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal-transduction pathways[J]. Int J Cancer, 2008, 123(11): 2543-2556. DOI: 10.1002/ijc.23821.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

TET1基因对肺癌细胞迁移和侵袭能力的影响

LncRNA FGD5-AS1通过调节miR-302b-3p/E2F1轴对胃癌细胞迁移及侵袭的影响

β-arrestin1在口腔鳞状细胞癌中的表达及其对细胞增殖、迁移、侵袭的作用

CPNE3调控非小细胞肺癌细胞增殖、迁移、侵袭及其相关机制研究

RNA传感器IFIH1对HPV阳性的宫颈癌细胞增殖、迁移和侵袭的影响