CCL2 promotes metastasis and epithelial–mesenchymal transition of non-small cell lung cancer via PI3K/Akt/mTOR and autophagy pathways

  • Hui Xu 1 ,
  • Jin Wang 2 ,
  • Murad Al-Nusaif 1 ,
  • Huipeng Ma 3 ,
  • Weidong Le , 1,4
Expand
  • 1. Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
  • 2. Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
  • 3. College of Medical Laboratory, Dalian Medical University, Dalian, China
  • 4. Institute of Neurology, Sichuan Academy of Medical Science-Sichuan Provincial Hospital, Medical School of UESTC, Chengdu, China
wdle@sibs.ac.cn

Received date: 04 Apr 2023

Revised date: 02 Sep 2023

Accepted date: 02 Oct 2023

Copyright

2023 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.

Abstract

In non-small cell lung cancer (NSCLC), metastasis is the most common phenotype, and autophagy plays a vital role in its regulation. However, there are limited data on how autophagy-related genes and metastasis-related genes affect NSCLC progression. Our goal was to identify the genes that regulate autophagy and metastasis in NSCLC, and to assess the underlying mechanisms in this current study. RNA sequencing data from public databases were used to screen differentially expressed autophagy- and metastasis-associated genes. Enrichment analyses and immune correlations were conducted to identify hub genes and potential regulating pathways in NSCLC. In this study, we found that CCL2 expression was highly expressed in NSCLC tissues and high CCL2 level was correlated with strong infiltration in lung tissues from NSCLC patients. Overexpression of CCL2 can enhance the metastasis of NSCLC cells in nude mice. Furthermore, CCL2 activated the PI3K/Akt/mTOR signalling pathway axis, promoted epithelial–mesenchymal transition (EMT), and blocked the autophagic flux in NSCLC cells. Therefore, our results indicate that CCL2 promotes metastasis and EMT of NSCLC via PI3K/Akt/mTOR axis and autophagy signalling pathways. We believe that CCL2 could be a probable target for the diagnosis and therapeutics of NSCLC, and this study may expand our understanding of lung cancer.

Cite this article

Hui Xu , Jin Wang , Murad Al-Nusaif , Huipeng Ma , Weidong Le . CCL2 promotes metastasis and epithelial–mesenchymal transition of non-small cell lung cancer via PI3K/Akt/mTOR and autophagy pathways[J]. Cell Proliferation, 2024 , 57(3) : e13560 . DOI: 10.1111/cpr.13560

1
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.

2
Miller KD, Nogueira L, Devasia T, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72(5):409-436.

3
Arbour KC, Riely GJ. Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review. JAMA. 2019;322(8):764-774.

4
Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239-252.

5
Li M, Zhang Q, Fu P, et al. Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. PLoS One. 2012;7(5):e37229.

6
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.

7
Gerdan L, Segedin B, Nagy V, et al. Brain metastasis from non-small cell lung cancer (NSCLC) prognostic importance of the number of involved extracranial organs. Strahlenther Onkol. 2014;190(1):64-67.

8
Valiente M, Obenauf AC, Jin X, et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014;156(5):1002-1016.

9
Wittig A, Moss RL, Sauerwein WAG. Glioblastoma, brain metastases and soft tissue sarcoma of extremities: candidate tumors for BNCT. Appl Radiat Isot. 2014;88:46-49.

10
Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer. 2011;11(2):135-141.

11
Roca H, McCauley LK. Inflammation and skeletal metastasis. Bonekey Rep. 2015;4:706.

12
Bald T, Quast T, Landsberg J, et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014;507(7490):109-113.

13
Craene BD, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97-110.

14
Wang J, Gong M, Fan X, Huang D, Zhang J, Huang C. Autophagy-related signaling pathways in non-small cell lung cancer. Mol Cell Biochem. 2022;477(2):385-393.

15
Guo W, Du K, Luo S, Hu D. Recent advances of autophagy in non-small cell lung cancer: from basic mechanisms to clinical application. Front Oncol. 2022;12:861959.

16
Marsh T, Debnath J. Autophagy suppresses breast cancer metastasis by degrading NBR1. Autophagy. 2020;16(6):1164-1165.

17
Zhang M, Liu S, Chua M-S, et al. SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway. Cell Death Dis. 2019;10(8):612.

18
Ren J, Hu Z, Niu G, et al. Annexin A1 induces oxaliplatin resistance of gastric cancer through au tophagy by targeting PI3K/AKT/mTOR. FASEB J. 2023;37(3):e22790.

19
Dong R, Zhang X, Liu Y, et al. Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via PI3K/AKT/mTOR pathway in diabetic kidney disease. Phytomedicine. 2023;112:154700.

20
Nymark P, Lindholm PM, Korpela MV, et al. Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines. BMC Genomics. 2007;8:62.

21
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284-287.

22
Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-D613.

23
Jia C, Qi H, Cheng C, et al. Alpha-synuclein negatively regulates Nurr1 expression through NF-kappaB-related mechanism. Front Mol Neurosci. 2020;13:64.

24
Ḣanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.

25
Xu H, Li Z, Guo Y, Peng X, Qin J. Probing the response of lung tumor cells to inflammatory microvascular endothelial cells on fluidic microdevice. Electrophoresis. 2017;38(2):311-319.

26
Lohmussaar K, Kopper O, Korving J, et al. Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids. Nat Commun. 2020;11(1):2660.

27
Dai J, Xu M, Wang Q, et al. Cooperation therapy between anti-growth by photodynamic-AIEgens and anti-metastasis by small molecule inhibitors in ovarian cancer. Theranostics. 2020;10(5):2385-2398.

28
Erasmus JC, Bruche S, Pizarro L, et al. Defining functional interactions during biogenesis of epithelial junctions. Nat Commun. 2016;7:13542.

29
Shih YV, Varghese S. Tissue engineered bone mimetics to study bone disorders ex vivo: role of bioinspired materials. Biomaterials. 2019;198:107-121.

30
Yang K, Wei M, Yang Z, et al. Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity. Cell Oncol (Dordr). 2020;43(6):1175-1190.

31
Liu Y, Wu L, Ao H, et al. Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer. Aging. 2019;11(23):11440-11462.

32
Ren Y, Cao L, Wang L, et al. Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFkappaB signaling. Cell Death Dis. 2021;12(10):858.

33
Xu C, Cao H, Sui Y, et al. CDCA4 suppresses epithelial-mesenchymal transtion (EMT) and metastasis in non-small cell lung cancer through modulating autophagy. Cancer Cell Int. 2021;21(1):48.

34
Fang S, Tang H, Li MZ, Chu JJ, Yin ZS, Jia QY. Identification of the CCL2 PI3K/Akt axis involved in autophagy and apoptosis after spinal cord injury. Metab Brain Dis. 2023;38:1335-1349.

35
Wang T, Zhan Q, Peng X, Qiu Z, Zhao T. CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel. Oncol Lett. 2018;16(1):1267-1274.

36
Tao Z, Jie Y, Mingru Z, et al. The Elk1/MMP-9 axis regulates E-cadherin and occludin in ventilator-induced lung injury. Respir Res. 2021;22(1):233.

37
Ling Z, Yang X, Chen X, Xia J, Cheng B, Tao X. CCL2 promotes cell migration by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma. J Oral Pathol Med. 2019;48(6):477-482.

38
White E. The role for autophagy in cancer. J Clin Invest. 2015;125(1):42-46.

39
Wang Y, Xiong H, Liu D, et al. Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. Autophagy. 2019;15(5):886-899.

40
Wang C, Yang Z, Xu E, et al. Apolipoprotein C-II induces EMT to promote gastric cancer peritoneal metastasis via PI3K/AKT/mTOR pathway. Clin Transl Med. 2021;11(8):e522.

Options
Outlines

/