A narrative review of the relationship between TGF-β signaling and gynecological malignant tumor

Abstract

Objective: This paper reviews the association between transforming growth factor-β (TGF-β) and its receptor and tumor, focusing on gynecological malignant tumors. we hope to provide more methods to help increase the potential of TGF-β signaling targeted treatment of specific cancers.

Background: The occurrence of a malignant tumor is a complex process of multi-step, multi-gene regulation, and its progression is affected by various components of the tumor cells and/or tumor microenvironment. The occurrence of gynecological diseases not only affect women's health, but also bring some troubles to their normal life. Especially when gynecological malignant tumors occur, the situation is more serious, which will endanger the lives of patients. Due to differences in environmental and economic conditions, not all women have access to assistance and treatment specifically meeting their needs. TGF-β is a multi-potent growth factor that maintains homeostasis in mammals by inhibiting cell growth and promoting apoptosis in vivo. TGF-β signaling is fundamental to inflammatory disease and favors the emergence of tumors, and it also plays an important role in immunosuppression in the tumor microenvironment. In the early stages of the tumor, TGF-β acts as a tumor inhibitor, whereas in advanced tumors, mutations or deletion of the TGF-β signaling core component initiate neogenesis.

Methods: Literatures about TGF-β and gynecological malignant tumor were extensively reviewed to analyze and discuss.

Conclusions: We discussed the role of TGF-β signaling in different types of gynecological tumor cells, thus demonstrating that targeted TGF-β signaling may be an effective tumor treatment strategy.

Keywords: Malignant tumor; SMAD; gynecology; signal transduction; transforming growth factor-β (TGF-β).

Figure 1

The role of TGF-β signaling pathway in cancer. In the SMAD-dependent pathway (right), TGF-β binds to TGFβR-II and phosphorylates TGFβR-I, which activates SMAD2 and SMAD3. The activated SMAD2/3 forms a complex with SMAD4, which enters the nucleus in the early and advanced stages of tumorigenesis, interacts with various transcription factors and transcription co-activators, and regulates the transcription of the target gene. SMAD7 antagonizes TGF-β-delivery signals by blocking SMAD2/3 activation and interfering with the formation of the SMAD2/3/4 complex. In the SMAD-independent pathway (left), TGF-β signaling can also regulate cellular responses through non-SMAD signaling pathways, such as p38/MAPK, ERK/MAPK, NF-κB, JNK, PI3K/AKT, and RhoA-Rock1, etc. TGF-β, transforming growth factor-β.

Figure 2

Tumor inhibitory function of TGF-β signaling. (A) TGF-β/β1 controls cell cycle progression by inhibiting oncogenic c-Myc, and this factor prevents the transcriptional activation of CDK inhibitors (p15 and p21) by interacting with MIZ1. TGF-β/β1 also directly activates p15 (inactivates CDK4/6) and p21 (inactivates CDK2) transcriptionally, which leads to cell cycle arrest at the G1-S boundary. (B) TGF-β/β1 regulates the growth, apoptosis, and genome stability of a variety of cells, however the exact molecular mechanism remains to be determined. TGF-β, transforming growth factor-β; CDK, cyclin-dependent kinase.