The role of cell cycle-related genes in the tumorigenesis of adrenal and thyroid neuroendocrine tumors

Abstract

The molecular mechanisms underlying adrenal and thyroid neuroendocrine tumors, including their tumorigenesis, progression, and metastasis, involve unique pathways regulating cell cycle progression. To better understand these mechanisms and pathways, extensive in-depth research on cell cycle-related genes is necessary. This review aims to describe and interpret current single-cell RNA sequencing studies on neuroblastoma, medullary thyroid cancer, and pheochromocytoma tumors. Our review summarizes differentially expressed cell cycle-related genes with distinct functions, highlighting their potential as therapeutic targets and components of panels used to determine tumor type or aggressiveness. Although some insights have been gained, there is still limited information on these topics, and further research is required to explore the regulatory mechanisms of these tumors.

Keywords: Adrenal gland; Cell cycle-related genes; Medullary thyroid cancer; Neuroblastoma; Neuroendocrine tumors; Pheochromocytoma; Thyroid gland; scRNA-seq.

Fig. 1

Differentially expressed cell cycle-related genes in neuroblastoma. CDK4, CCNA2, and NR2F2 promote S/G2 phase progression. CCNA2, CCNB1, CDK1, CENPF, FOXD3, and TOP2A promote G2/M checkpoint transition. CTCF and RAD21 promote G2 phase progression. RAD21, PCNA, and MCM3 promote the S phase progression, while FOXD3 inhibits S phase progression. TOP2A, CKAP2, and UBE2C promote M phase progression. CCNB2 and NUF2 promote the spindle checkpoint transition. CTCF and JUN promote G1 phase progression, while CDKN1C promotes G1 phase arrest. MYCN, EZH2, and EGFR promote G1/S checkpoint progression, while HOXC9, E2F7, and E2F8 block the transition. There are genes with unknown effects on cell cycle phases like TNFRSF1A, TIMP3, and S100B. The green color represents upregulation and progression of the phase or transition; the red color represents downregulation and cell cycle arrest.

Fig. 2

Differentially expressed cell cycle-related genes in pheochromocytoma and their role in the cell cycle regulation. TOP2A promotes G2/M checkpoint transition and M phase progression, while RGS4 induces G2/M checkpoint failure. POMC, TMEM176A, GNAS and CALM2 promote G1/S checkpoint transition, while DLK1, RBP1, UCHL1, DIRAS3, and RGS5 block it. There are genes with unknown functions on cell cycle phases: TMEM176B, STC1, PFKP, and CRH. The green color represents upregulation and progression of the phase or transition; the red color represents downregulation and cell cycle arrest.

Fig. 3

Differentially expressed cell cycle-related genes in MTC. GPI and PPIH promote G2/M checkpoint transition, while CDH1 blocks the transition. PPIH promotes S phase progression. ARF1 inhibits M phase progression through the COPA gene interaction. CDH1 promotes G1 phase arrest. AIMP, EPCAM, RICTOR, RET, and PGK1 genes promote G1/S checkpoint progression. BCL2 inhibits G1/S checkpoint transition and blocks G1 phase progression. HLA-E promotes the senescent state of cells. There are genes with unknown effects on cell cycle phases like CEACAM5, MAP3K4, PROM1, and SDHA. The green color represents upregulation and progression of the phase or transition; the red color represents downregulation and cell cycle arrest.

Fig. 4

Сomplex interplay between cell cycle-related genes and their influence on various signaling pathways in NETs. EPCAM, BCL2, STMN1, and MYCN influence pathways involved in epithelial-to-mesenchymal transition (EMT) [[235], [236], [237]], with MYCN exerting a particular influence on the Wnt/β-catenin pathway [238]. Additionally, MYCN influences the MYCN-PARP-DNA damage response (DDR) pathway and the p-53 signaling pathway [239]. EZH2 and UCHL1 also interact with the p53 signaling pathway [240,241]. BCL2 further influences the IL-6/JAK/STAT3 signaling pathway [235]. CDK4 and UCHL1 modulate the CDK4/6-pRB-E2F pathway [241], with CDK4 acting as an inhibitor [242]. STMN1 enhances the PI3K/AKT/mTOR pathway [243], while EGFR, RET, RICTOR, and UCHL1 exert distinct, yet undefined, effects on this pathway [241,[244], [245], [246], [247]]. RET additionally influences the MAPK/ERK and c-Jun-NH2-kinase (JNK) pathways [244]. DLK1 and EGFR impact the PI3K/AKT/mTOR and MAPK/ERK pathways [245,248], with DLK1 acting as an inhibitor of both [249,250]. СEACAM5 enhances the MAPK/ERK pathway [251]. The green color represents activation of the pathway, the red color represents inhibition of the pathway, the white color indicates genes with insufficient information for precise evaluation as enhancers or inhibitors, and the gray color indicates signaling pathways.