Tristetraprolin, a Potential Safeguard Against Carcinoma: Role in the Tumor Microenvironment

Abstract

Tristetraprolin (TTP), a well-known RNA-binding protein, primarily affects the expression of inflammation-related proteins by binding to the targeted AU-rich element in the 3' untranslated region after transcription and subsequently mediates messenger RNA decay. Recent studies have focused on the role of TTP in tumors and their related microenvironments, most of which have referred to TTP as a potential tumor suppressor involved in regulating cell proliferation, apoptosis, and metastasis of various cancers, as well as tumor immunity, inflammation, and metabolism of the microenvironment. Elevated TTP expression levels could aid the diagnosis and treatment of different cancers, improving the prognosis of patients. The aim of this review is to describe the role of TTP as a potential safeguard against carcinoma.

Keywords: RNA binding protein; carcinoma; potential safeguard; tristetraprolin (TTP); tumor microenvironment (TME).

Figure 1

TTP/ZFP36 expression in cancer and normal tissues analyzed by GEPIA. Compared with normal tissues analyzed by GEPIA; TTP mRNA expression is significantly lower in the tissues of most forms of carcinoma. ACC, Adrenocortical carcinoma; BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; CESC, Cervical squamous cell carcinoma; CHOL, Cholangiocarcinoma; COAD, Colon adenocarcinoma; DLBC, Lymphoid Neoplasm Diffuse Large B-cell Lymphoma; ESCA, Esophageal carcinoma; GBM, Glioblastoma multiforme; HNSC, Head and Neck squamous cell carcinoma. KICH, Kidney Chromophobe; KIRC, Kidney renal clear cell carcinoma; KIRP, Kidney renal papillary cell carcinoma; LAML, Acute Myeloid Leukemia; LGG, Brain Lower Grade Glioma; LIHC; liver hepatocellular carcinoma; LUAD; lung adenocarcinoma; LUSC; lung squamous cell carcinoma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, Pheochromocytoma and Paraganglioma; PRAD, Prostate adenocarcinoma; READ, Rectum adenocarcinoma; SARC, Sarcoma; SKCM, Skin Cutaneous Melanoma; STAD, Stomach adenocarcinoma; TGCT, Testicular Germ Cell Tumors; THCA, Thyroid carcinoma; THYM, Thymoma; UCEC, Uterine Corpus Endometrial Carcinoma; UCS, Uterine Carcinosarcoma (17).

Figure 2

Types of TTP/ZFP36. TTP/ZFP36 along with ZFP36L1 and L2, all members of the ZFP36 family share similar structures and functions in mammals, while L3 is found only in rodents.

Figure 3

Role of TTP in carcinoma. (A) TTP inhibits Cyclin B expression by inducing the arrest of cell cycle from Phase G1 to S or G2 to M, Cyclin D expression in Phase G1, and Wee1 expression from Phase S to G2, thus suppressing the proliferation of cancer cells. (B) The transcription of TTP, induced by TGF-β and HADC inhibitor, binds with the other transcription factors, Smad and EGR1. Subsequently, TTP inhibits COX-2 expression and suppresses the proliferation of cancer cells. (C) Two cytoplasmic signaling pathways of TTP are involved in the apoptosis of tumor cells.

Figure 4

The dynamic change in the tumor microenvironment (TME) when TTP is downregulated. When TTP expression decreases in tumor cells, the primary tumor invades the basement membrane. Moreover, an increased number of blood and lymph vessels aids tumor metastasis. In the microenvironment, the increasing inflammatory response, immune escape, and energy also provide a favorable environment for tumor progression.

Figure 5

Mechanism of TTP-dependent anti-tumor immunity in the tumor microenvironment (TME). PD-1, a receptor expressed on T lymphocytes, interacts with its ligand PD-L1 on target cells, recognizing healthy cells and preventing induced cell death. However, tumor cells can express PD-L1 and interact with PD-1 on T lymphocytes. T lymphocytes infiltrate Treg cells, evading the tumor immunosurveillance to allow distant metastasis. Consequently, TTP recognizes tumor cells, destabilizes PD-L1 mRNA, and decreases its expression. Thus, T lymphocytes can recognize tumor cells and secrete CD8⁺ cells to promote tumor cell death.