Page 100 - TD-3-4

Tumor Discovery Bioinformatics insights into CCL2 mutations

7 Centre for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai,
Tamil Nadu, India
8 Enzymoics, 7 Peterlee Place, Hebersham, Novel Global Community Educational Foundation, NSW, Australia
(This article belongs to the Special Issue: Colorectal Cancer: Best Tools for Diagnosis to Management Strategies)

1. Introduction Moreover, MCP-1 produced by human gastric carcinoma
cells plays a crucial role in angiogenesis. It attracts and
Chemokine C-C motif ligand 2 (CCL2), also known as activates macrophages, which then aid in forming new
monocyte chemoattractant protein 1 (MCP-1) or small blood vessels and promote tumor growth. MCP-1
17
inducible cytokine A2, is an important cytokine in the has a limited role in eliciting an immune response in
CC chemokine family. CCL2 adopts a β-trefoil fold, renal cell carcinomas, as assessed by the parameters
1
which is a common protein fold that provides plasticity analyzed in this study. The simultaneous induction of
18
for recognizing various targets. Monomeric CCL2 binds
2
to its receptor, C-C motif chemokine receptor 2 (CCR2), tumor necrosis factor-alpha (TNF-α), urokinase-type
through a single, topologically novel binding site. plasminogen activator, interleukin (IL)-8, and MCP-1
3
CCL2 penetrates the extracellular portion of the CCR2 can enhance the interaction of tumor and inflammatory
transmembrane domain and interacts with the receptor cells, thereby increasing cytotoxicity and promoting
19
through its N-terminal glutamine. There are numerous tumor suppression. MCP-1 can potentiate the effects of
hydrophobic and polar interactions between CCL2 and bacterial endotoxins by activating macrophages to become
20
the Gα-protein of the CCR2 receptor complex, which tumoricidal, potentially suppressing metastasis. The
contribute to the receptor’s constitutive activity. 4 chemokine MCP-1 plays an important role in promoting
tumor progression and angiogenesis across various cancer
CCL2 plays a crucial role in regulating cellular types, including breast, ovarian, esophageal, and gastric
mechanics by attracting monocytes, memory T-cells, carcinomas. MCP-1 production by tumor cells contributes
and dendritic cells to inflammation sites resulting from to the recruitment and activation of tumor-associated
tissue injury or infection. This small cytokine is primarily macrophages, supporting cancer growth and metastasis.
5
secreted by monocytes, macrophages, and dendritic
cells and is involved in various physiological processes, Computational analysis has become increasingly
including immune cell recruitment, antitumor activity, vital for identifying harmful mutations and predicting
and granuloma formation. CCL2 interacts with cell the effects of missense mutations on protein structures
6
surface receptors, such as CCR2 and CCR4, and exhibits and functions. This type of analysis is now a key tool in
21
chemotactic activity for monocytes and basophils. Its designing new drugs and therapies for genetic diseases.
7
effects extend to diseases characterized by monocytic In this study, we evaluated the potential significance
infiltrates, such as psoriasis, rheumatoid arthritis, of mutations in CCL2 that can impact its protein
atherosclerosis, and certain cancers. In cancer, CCL2 functions and ligand interactions. Initially, we used
has been demonstrated to promote cell proliferation, various computational algorithms, including meta-single
22
23
migration, and metastasis, underscoring its potential as a nucleotide polymorphism (SNP), PolyPhen-2, and
24
therapeutic target for cancer treatment. 8,9 Pmut, to categorize harmful mutations. We further
employed the Functional Analysis through Hidden Markov
Chemokines can induce the release of stored Models (FATHMM) server to identify specific genetic
promalignant chemokines from breast tumor cells, variants associated with cancer development or initiation
highlighting the substantial tumor-promoting role of among disease-causing mutations. This approach allowed
chemokine coexpression in breast cancer progression. 10-12 us to distinguish between cancer-promoting mutations
Epithelial ovarian cancer cells produce MCP-1, which is and those related to other disease phenotypes, providing
likely the major source of this chemokine. This production valuable insights into the specific role of certain variants in
may contribute to the accumulation of tumor-associated cancer pathogenesis. In addition to the sequence-based
25
macrophages, which can subsequently influence tumor
behavior. 13,14 Cancer cells and macrophages interact to analysis, we employed structure-based computational
27
28
26
promote tumor angiogenesis, a crucial process in cancer tools, such as mCSM, SDM, and DUET, to predict the
progression. Specifically, MCP-1 has been linked to the impact of the identified mutations on the structure and
progression of human esophageal carcinoma by facilitating stability of the corresponding proteins.
angiogenesis, enhancing macrophage recruitment, and One missense mutation in CCL2 was selected based
promoting the development of new blood vessels. 15,16 on its cancer association for further investigation. The

Volume 3 Issue 4 (2024) 2 doi: 10.36922/td.3891