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Review
. 2022 Jan 29:2022:4107433.
doi: 10.1155/2022/4107433. eCollection 2022.

CGRP: A New Endogenous Cell Stemness Maintenance Molecule

Xiaoting Lv  1 , Qingquan Chen  2 , Shuyu Zhang  3 , Feng Gao  4 , Qicai Liu  5
Affiliations
Review

CGRP: A New Endogenous Cell Stemness Maintenance Molecule

Xiaoting Lv et al. Oxid Med Cell Longev. .

Abstract

Stem cells have the ability of self-replication and multidirectional differentiation, but the mechanism of how stem cells "maintain" this ability and how to "decide" to give up this state and differentiate into cells with specific functions is still unknown. The Nobel Prize in physiology and medicine in 2021 was awarded to "temperature and tactile receptor," which made the pain receptor TRPV1-calcitonin gene-related peptide (CGRP) pathway active again. The activation and blocking technology of CGRP has been applied to many clinical diseases. CGRP gene has complex structure and transcription process, with multiple methylation and other modification sites. It has been considered as a research hotspot and difficulty since its discovery. Drug manipulation of TRPV1 and inhibition of CGRP might improve metabolism and prolong longevity. However, whether the TRPV1-neuropeptide-CGRP pathway is directly or indirectly involved in stem cell self-replication and multidirectional differentiation is unclear. Recent studies have found that CGRP is closely related to the migration and differentiation of tumor stem cells, which may be realized by turning off or turning on the CGRP gene expression in stem cells and activating a variety of ways to regulate stem cell niches. In this study, we reviewed the advances in researches concentrated on the biological effects of CGRP as a new endogenous switching of cell stemness.

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Conflict of interest statement

The authors have no competing interests to declare.

Figures

Figure 1
Figure 1
Diagram of the structures for both the CALCA and CALCB genes. Both the CALCA and CALCB genes contain all six exons, with multiple methylation and other modification sites. (a) Multiple methylation sites of CALCA promoter with a large area of CpG in the 5′ end were found in different types of bacterial preterm sepsis (-716 bp, -719 bp, -728 bp, -733 bp, -739 bp, -769 bp, -771 bp, and -796 bp) and pancreatic ductal adenocarcinoma and its paracancer (-23 bp, -247 bp), and the methylation of CALCA exon 1 was related to fluoride exposure. CALCA enhancer could also be activated by upstream stimulating factor (USF) and forkhead protein Foxa2. Four novel polymorphic alleles were found in neurological or psychiatric disease: two (g.979G>A and g.4218T>C) represented single nucleotide polymorphisms (SNPs), one consisted of two coupled SNPs in close vicinity to each other (g.1210T>C and g.1214C>G), and one was an intronic 16 bp microdeletion (2919-2934del16). One of the SNPs (g.4218T>C) causes a nonsynonymous amino acid change (Leu66Pro) in the third exon, an exon common to both procalcitonin and pro-a-CGRP. (b) Multiple methylation sites of CALCB promoter with a large area of CpG in the 5′ end were found in pancreatic ductal adenocarcinoma and its paracancer (-17 bp, -36 bp, -54 bp, -60 bp, -67 bp, -161 bp, -170 bp, -172 bp, -213 bp, -217 bp, -221 bp, -225 bp, -227 bp, -247 bp, -278 bp, -286 bp, -346 bp, and -349 bp). Promoter polymorphisms of CALCB gene (rs11603873 T/C and rs79501047 A/G) are common in the Han population, and the rs11603873 C genotype has a high risk of salivary adenoid cystic carcinoma compared with the rs11603873 T genotype.
Figure 2
Figure 2
CGRP secreted by TRPV1 neurons in the stem cell niches promotes the proliferation and differentiation of AT II cells. Stem cell niches are specialized microenvironment composed of different types of cells, extracellular matrix proteins, and growth factors. Promoter DNA methylation regulates CGRP expression. CGRP secreted by TRPV1 neurons in the stem cell niches takes effect on lung pluripotent stem cells to induce the proliferation and differentiation of AT II cells through downstream pathways, such as Sonic hedgehog signaling pathway and Wnt signaling pathway.
Figure 3
Figure 3
High CGRP expression promotes the malignant transformation of PNECs through the SHH signaling pathway. PNECs regulate group 2 innate lymphoid cells (ILC2s) through CGRP in small cell lung cancer which may affect the immune status of the tumor microenvironment. Moreover, CGRP protects stem cells from apoptosis by blocking the G0/G1 phase of the cell cycle to S phase through the SHH signaling pathway.
Figure 4
Figure 4
Abnormal CGRP expression promotes cell cycle disorder and promotes the occurrence of pancreatic cancer. The helicase Prp2 (blue) and the coactivator Spp2 (purple) combine stably with the anchor molecules on the spliceosome, so as to binding Prp2 to the activated spliceosome and allowing a greater role for Prp2. CGRP pre-mRNA (red) is loaded into the characteristic channel between the N- and C-halves of Prp2. The process of ATP binding and hydrolyzation or trypsin (green, specific high expression in the pancreas) triggers Prp2 to move into sensitive binding site of trypsin, driving pre-mRNA to move unidirectionally and gradually towards its 3′ end. By CGRP disturbing cell cycle, abnormal shearing breaks the genetic stability and amplifies oncogenic signals, whose function is similar to that of an essential translator and amplifier in the carcinogenic pathway.
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