SERPINA3

SERPINA3 Full Name

serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3

SERPINA3 Introduction

SERPINA3, also known as serpin peptidase inhibitor clade A member 3, is a member of the serine protease inhibitor family that plays a pivotal role in regulating proteolytic activity during physiological and pathological processes. Traditionally recognized as an acute-phase protein, SERPINA3 has emerged as a critical mediator linking inflammation to cancer development. Research has shown that it actively participates in the transition from an inflammatory microenvironment to a tumor-promoting environment by modulating key signaling pathways such as PI3K/AKT and MAPK/ERK. This regulation promotes cellular proliferation, survival, and resistance to apoptosis, positioning SERPINA3 as a potential "fifth column" that can undermine normal tissue defenses and facilitate disease progression, making it an attractive target for diagnostic and therapeutic strategies.

In cancer contexts, SERPINA3 exhibits complex, tissue-specific functions. In aggressive cancers like triple-negative breast cancer, SERPINA3 is often upregulated and drives malignant behaviors, including enhanced cell proliferation, migration, and invasion. Mechanistically, it promotes epithelial-mesenchymal transition (EMT) and upregulates oncogenic factors such as EZH2, contributing to chemoresistance, particularly against platinum-based therapies. Conversely, in lung cancer, where its expression is typically lower, overexpression of SERPINA3 has been shown to inhibit tumor progression. By enhancing the activity of tumor suppressor SPOP and suppressing NF-κB signaling, SERPINA3 reduces lung cancer cell proliferation and invasion while increasing apoptosis and sensitivity to targeted therapies like osimertinib. These findings highlight the dualistic nature of SERPINA3, acting either as a tumor promoter or suppressor depending on the cellular and molecular context.

Beyond its role in solid tumors, SERPINA3 also impacts the tumor immune microenvironment, as seen in castration-resistant prostate cancer (CRPC). Here, low SERPINA3 levels correlate with disease progression, whereas its overexpression suppresses tumor growth by upregulating CXCL2, thereby recruiting M1 macrophages that exert anti-tumor effects. This immunomodulatory function emphasizes SERPINA3's potential as a therapeutic target not only for directly modulating tumor cell behavior but also for reshaping the tumor microenvironment to enhance anti-cancer immunity. Collectively, these studies underscore SERPINA3 as a multifaceted biomolecule with significant implications in inflammation, cancer progression, and therapy resistance, making it a focal point for translational research and drug development.

Alternate Names for SERPINA3

SERPINA3; serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3; ACT; AACT; GIG24; GIG25; alpha-1-antichymotrypsin; serpin A3; growth-inhibiting protein 24; growth-inhibiting protein 25

• 1.De Mezer M, et al.; SERPINA3: Stimulator or Inhibitor of Pathological Changes. Biomedicines. 2023, 11(1):156.
  2.Zhang Y, et al.; Overexpression of SERPINA3 promotes tumor invasion and migration, epithelial-mesenchymal-transition in triple-negative breast cancer cells. Breast Cancer. 2021, 28(4):859-873.