Cell Behavior of Non-Small Cell Lung Cancer Is at EGFR and MicroRNAs Hands

Abstract

Lung cancer is a complex disease associated with gene mutations, particularly mutations of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and epidermal growth factor receptor (EGFR). Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major types of lung cancer. The former includes most lung cancers (85%) and are commonly associated with EGFR mutations. Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, and osimertinib, are effective therapeutic agents in EGFR-mutated NSCLC. However, their effectiveness is limited by the development (acquired) or presence of intrinsic drug resistance. MicroRNAs (miRNAs) are key gene regulators that play a profound role in the development and outcomes for NSCLC via their role as oncogenes or oncosuppressors. The regulatory role of miRNA-dependent EGFR crosstalk depends on EGFR signaling pathway, including Rat Sarcoma/Rapidly Accelerated Fibrosarcoma/Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 (Ras/Raf/MEK/ERK1/2), Signal Transducer and Activator of Transcription (STAT), Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-kB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase 1 (JAK1), and growth factor receptor-bound protein 2 (GRB2). Dysregulated expression of miRNAs affects sensitivity to treatment with EGFR-TKIs. Thus, abnormalities in miRNA-dependent EGFR crosstalk can be used as diagnostic and prognostic markers, as well as therapeutic targets in NSCLC. In this review, we present an overview of miRNA-dependent EGFR expression regulation, which modulates the behavior and progression of NSCLC.

Revisiting the Syndecans: Master Signaling Regulators with Prognostic and Targetable Therapeutic Values in Breast Carcinoma

“…Several studies underscored the clinical significance of miRNAs serving as diagnostic, prognostic, and predictive markers for a wide range of tumor entities [ 132 , 133 ]. Mechanistically, dysregulated miRNA expression via regulation of their targets can affect hallmarks of cancer, namely cell proliferation, apoptosis, adhesion, migration, invasion, and metastasis, as is evident from both in vitro and in vivo studies [ 129 , 134 , 135 , 136 , 137 , 138 ].…”

Emerging Role of Noncoding RNAs in EGFR TKI-Resistant Lung Cancer

“…Acquired drug resistance has long been a major hurdle hindering the therapeutic effect of EGFR TKIs [ 6 , 7 , 8 ]. Accumulating evidence has indicated that ncRNAs, especially circRNAs, lncRNAs and miRNAs, play a vital role in EGFR TKI-resistant lung cancer via alternative signaling pathway modulation [ 10 , 36 ]. Here, ncRNAs involved in essential signaling pathways downstream and parallel pathways of EGFR are discussed in detail ( Figure 2 ).…”

“…In cancer biology, NF-κB has major functions as a proliferative stimulator and apoptotic suppressor in tumor cells, which also mediates drug resistance [ 70 ]. Notably, NF-κB not only independently sustains EGFR TKI resistance but also serves as an effector downstream of the JAK/STAT signaling pathway to enhance EGFR TKI resistance [ 36 ]. NcRNAs involved in NF-κB pathway modulation are primarily examined for their ability to target upstream regulators.…”

“…The advent of RNA-sequencing and analytical technologies has strongly enhanced the exploration of ncRNA biological functions and pathophysiological roles. On this account, ncRNAs are pyramidally utilized to illustrate the tumorigenesis and progression of malignancies, creating the conditions for in-depth research on the mechanisms of EGFR TKI-resistant lung cancer [ 10 , 36 ]. Emerging evidence has also shown that certain ncRNAs play an indispensable role in the regulation of critical signal pathways inducing EGFR TKI resistance, including PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, JAK/STAT and EMT [ 38 , 58 , 61 , 68 , 77 ].…”

EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer

“…These aberrations induce cancer cells to stimulate adjacent stromal cells and augment the release of ECM proteins, growth factors, cytokines, angiogenic factors, and proteolytic enzymes into tumor stroma to form a tumor-supportive microenvironment ( Figure 1 ) ( 20 , 21 ). The development of resistance to EGFR tyrosine kinase inhibitors (TKIs) is still a critical problem in lung cancer, and the underlying mechanisms remain fully unexplored ( 22 ). Although TKI-induced or –selected genetic alterations are known to cause chemoresistance, other poorly understood mechanisms in tumor cells can drive this resistance.…”