Next Article in Journal
GSK3 as a Regulator of Cytoskeleton Architecture: Consequences for Health and Disease
Next Article in Special Issue
Metavariables Resuming Host Immune Features and Nodal Involvement Are Associated with Oncological Outcomes in Oral Cavity Squamous Cell Carcinoma
Previous Article in Journal
Electroconvulsive Shock, but Not Transcranial Magnetic Stimulation, Transiently Elevates Cell Proliferation in the Adult Mouse Hippocampus
Previous Article in Special Issue
Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Comprehensive Integrative Analysis Reveals the Association of KLF4 with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment

1
Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
2
Centre for Interdisciplinary Research in Basic Sciences, Srinivasa Ramanujan Block, Jamia Millia Islamia, New Delhi 110025, India
3
Multidisciplinary Centre for Advance Research and Studies, Jamia Millia Islamia, New Delhi 110025, India
4
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
*
Author to whom correspondence should be addressed.
Cells 2021, 10(8), 2091; https://doi.org/10.3390/cells10082091
Submission received: 8 July 2021 / Revised: 7 August 2021 / Accepted: 12 August 2021 / Published: 14 August 2021
(This article belongs to the Collection Trends and Advances in Tumor Immunology)

Abstract

Macrophage polarization and infiltration to the tumor microenvironment (TME) is a critical determining factor for tumor progression. Macrophages are polarized into two states—M1 (pro-inflammatory, anti-tumorigenic and stimulated by LPS or IFN-γ) and M2 (anti-inflammatory pro-tumorigenic and stimulated by IL-4) phenotypes. Specifically, M2 macrophages enhance tumor cell growth and survival. Recent evidences suggest the pivotal role of microRNAs in macrophage polarization during the development of Non-small cell lung cancer (NSCLC), thus proposing a new therapeutic option to target lung cancer. In silico analysis determined cogent upregulation of KLF4, downregulation of IL-1β and miR-34a-5p in NSCLC tissues, consequently worsening the overall survival of NSCLC patients. We observed a significant association of KLF4 with macrophage infiltration and polarization in NSCLC. We found that KLF4 is critically implicated in M2 polarization of macrophages, which, in turn, promotes tumorigenesis. KLF4 expression correlated with miR-34a-5p and IL-1β in a feed-forward loop (FFL), both of which are implicated in immune regulation. Mechanistic overexpression of miR-34a-5p in macrophages (IL-4 stimulated) inhibits KLF4, along with downregulation of ARG1, REL-1MB (M2 macrophage specific markers), and upregulation of IL-1β, IL-6, (M1 macrophage specific markers), demonstrating macrophage polarization switch from M2 to M1 phenotype. Moreover, co-culture of these macrophages with NSCLC cells reduces their proliferation, wound healing, clonogenic capacity and enhanced NO-mediated apoptosis. Further, transfection of miR-34a-5p in NSCLC cells, also degrades KLF4, but enhances the expression of KLF4 regulated genes—IL-1β, IL-6 (pro-inflammatory mediators), which is further enhanced upon co-culture with IL-4 stimulated macrophages. Additionally, we observed a significant increase in i-NOS/NO content upon co-culture, suggesting polarization reversion of macrophages from M2 to M1, and eventually leading to anti-tumor effects. Our findings thus show a significant role of KLF4 in tumorigenesis and TAM polarization of NSCLC. However, miR-34a-5p mediated targeting of these molecular networks will provide a better therapeutic intervention for NSCLC.
Keywords: KLF4; tumor-associated macrophages (TAMs); tumor microenvironment (TME); non-small cell lung cancer (NSCLC); macrophage polarization; IL-1β; miR-34a-5p KLF4; tumor-associated macrophages (TAMs); tumor microenvironment (TME); non-small cell lung cancer (NSCLC); macrophage polarization; IL-1β; miR-34a-5p
Graphical Abstract

Share and Cite

MDPI and ACS Style

Arora, S.; Singh, P.; Ahmad, S.; Ahmad, T.; Dohare, R.; Almatroodi, S.A.; Alrumaihi, F.; Rahmani, A.H.; Syed, M.A. Comprehensive Integrative Analysis Reveals the Association of KLF4 with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment. Cells 2021, 10, 2091. https://doi.org/10.3390/cells10082091

AMA Style

Arora S, Singh P, Ahmad S, Ahmad T, Dohare R, Almatroodi SA, Alrumaihi F, Rahmani AH, Syed MA. Comprehensive Integrative Analysis Reveals the Association of KLF4 with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment. Cells. 2021; 10(8):2091. https://doi.org/10.3390/cells10082091

Chicago/Turabian Style

Arora, Shweta, Prithvi Singh, Shaniya Ahmad, Tanveer Ahmad, Ravins Dohare, Saleh A. Almatroodi, Faris Alrumaihi, Arshad Husain Rahmani, and Mansoor Ali Syed. 2021. "Comprehensive Integrative Analysis Reveals the Association of KLF4 with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment" Cells 10, no. 8: 2091. https://doi.org/10.3390/cells10082091

APA Style

Arora, S., Singh, P., Ahmad, S., Ahmad, T., Dohare, R., Almatroodi, S. A., Alrumaihi, F., Rahmani, A. H., & Syed, M. A. (2021). Comprehensive Integrative Analysis Reveals the Association of KLF4 with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment. Cells, 10(8), 2091. https://doi.org/10.3390/cells10082091

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop