Introduction

Cancer remains a formidable global public health challenge due to its high mortality rates. Among various cancers, oral cancer is notable for its increasing prevalence and complexity. Oral squamous cell carcinoma (OSCC), the most common form, presents significant diagnostic and therapeutic challenges. Since early-stage oral cancer often lacks significant symptoms, many cases are diagnosed at advanced stages, resulting in poor prognosis due to limited treatment options.

PA28γ, also known as REGγ or PSME3, is a member of the proteasome activator family that has garnered attention for its roles in cancer biology. While initially identified in the serum of a systemic lupus erythematosus patient, PA28γ has been implicated in multiple cancers, including breast, prostate, thyroid, non-small-cell lung, renal cell carcinoma, and pancreatic cancers. Despite the ongoing research, the detailed mechanisms by which PA28γ impacts cancer progression and patient outcomes remain elusive. This article will elucidate the functions of PA28γ in oral cancer, focusing on its role in tumorigenesis, potential as a biomarker, and therapeutic target.

PA28γ and the Proteasome System

The proteasome system is crucial for maintaining physiological functions and homeostasis by degrading proteins in cells. Dysfunction in this system can lead to various diseases, including cancer. In higher eukaryotes, approximately 80-90% of protein degradation is mediated by the proteasome. The proteasome system involves different complexes, including the 20S core, which can form complexes with PA700 (19S), PA28/REG (11S), and PA200.

Fig. 1 Proteasome degradation system and biological functions of PA28γ (Xu X.; et al. 2015).

PA28γ is one of the PA28 family members, it is distinct from other proteasome activators such as PA28α and PA28β and promotes protein degradation in an ATP- and ubiquitin-independent manner through its association with the 20S core proteasome. This unique pathway underscores the importance of PA28γ in regulating cellular processes, including the degradation of proteins involved in cell cycle control, proliferation, migration, invasion, angiogenesis, and metastasis, especially in cancer cells.

PA28γ in Oral Cancer

Tumorigenesis and Cell Proliferation

PA28γ's involvement in cancer biology is multifaceted, influencing several aspects of tumorigenesis. Its overexpression has been documented in various cancers, including OSCC, where it regulates cell proliferation and migration. High levels of PA28γ facilitate the degradation of key cell cycle regulators such as p21 and p53, which are critical for controlling the G1-S phase transition. This degradation disrupts normal cell cycle progression, promoting uncontrolled cell proliferation, a hallmark of cancer.

In OSCC, PA28γ's overexpression has been linked to enhanced migratory abilities of cancer cells. Knockdown studies have demonstrated that reducing PA28γ levels leads to G0/G1 cell cycle arrest, increased apoptosis, and decreased cell viability. This arrest is largely due to the accumulation of p21 and the activation of caspase-3, a key apoptotic enzyme. These findings suggest that targeting PA28γ could impede OSCC progression by restoring normal cell cycle controls and inducing apoptosis.

Angiogenesis

Angiogenesis, the formation of new blood vessels, is vital for tumor growth and metastasis as it provides the necessary nutrients and oxygen to proliferating cancer cells. PA28γ has been implicated in promoting angiogenesis in OSCC through the activation of the NF-κB signaling pathway, which enhances the secretion of pro-angiogenic factors such as interleukin-6 (IL-6) and chemokine (C-C motif) ligand 2 (CCL2). These factors stimulate endothelial cells to form new blood vessels, supporting tumor growth and facilitating metastasis.

Metastasis

Metastasis is the primary cause of mortality in cancer patients, including those with oral cancer. PA28γ contributes to metastasis by regulating epithelial-mesenchymal transition (EMT), a process where epithelial cells acquire mesenchymal traits, enhancing their migratory and invasive capabilities. PA28γ activates the transforming growth factor-β (TGF-β) signaling pathway, which reduces the expression of epithelial markers like E-cadherin while upregulating mesenchymal markers such as ZEB1 and Snail. This shift facilitates cancer cell detachment from the primary tumor and invasion into surrounding tissues, a critical step in metastasis.

In clinical studies, high PA28γ expression has been correlated with advanced tumor stages, lymph node metastasis, and poor prognosis in OSCC patients. These findings underscore the potential of PA28γ not only as a biomarker for early diagnosis and prognosis but also as a therapeutic target to mitigate metastasis.

PA28γ as a Biomarker for Oral Cancer

The need for reliable biomarkers in cancer diagnosis and prognosis is paramount due to the heterogeneity of tumors. PA28γ shows promise as a novel biomarker for oral cancer for several reasons:

Expression Levels

PA28γ is markedly upregulated in OSCC compared to normal tissues. This upregulation correlates with higher tumor, node, and metastasis (TNM) stages and poorer overall survival rates in patients, indicating its potential as a prognostic marker.

Tumor Progression

PA28γ plays a critical role in cell proliferation, invasion, and metastasis. Its involvement in degrading key regulatory proteins and activating oncogenic pathways such as NF-κB, Wnt/β-catenin, and TGF-β/Smad further supports its significance in tumor biology.

Detection in Serum

PA28γ can be detected in human serum, providing a non-invasive means for early diagnosis and monitoring of cancer progression. This detection capability offers a practical approach for incorporating PA28γ into standard diagnostic and prognostic protocols.

Given these attributes, PA28γ holds the potential for integration into clinical practice, aiding in the early detection of oral cancer, prognostic assessment, and therapy stratification.

Therapeutic Targeting of PA28γ in Oral Cancer

The role of PA28γ in oral cancer makes it an attractive target for therapeutic intervention. By modulating PA28γ activity, it may be possible to impede cancer progression and enhance treatment outcomes. Several strategies to target PA28γ in cancer therapy include:

Inhibition of PA28γ Expression

Reducing PA28γ levels through genetic knockdown or pharmacological inhibitors has shown promise in preclinical studies. For instance, glucosamine and tetrandrine have been reported to downregulate PA28γ expression, induce apoptosis, and arrest the cell cycle in prostate and hepatocellular carcinoma cells, respectively [31,40]. Similar approaches could be explored in OSCC to determine their efficacy in reducing tumor growth and metastasis.

Modulation of Post-Translational Modifications

PA28γ activity is regulated by post-translational modifications such as acetylation, phosphorylation, and SUMOylation. Targeting these modifications could alter PA28γ function and its interaction with other proteins. For example, SIRT1-mediated deacetylation of PA28γ at K195 modulates its activity, suggesting that targeting acetylation might be a viable strategy to modulate PA28γ function in cancer cells.

Combination Therapy

PA28γ inhibition could be combined with existing treatments such as chemotherapy and radiotherapy to enhance their efficacy. Depleting PA28γ has been shown to increase chemosensitivity to agents like sorafenib and cisplatin in renal cell carcinoma and breast cancer, respectively. Similar combination strategies could be employed in OSCC to improve patient outcomes.

Conclusion

PA28γ plays a pivotal role in the progression of oral cancer by regulating cell proliferation, angiogenesis, and metastasis. Its overexpression correlates with advanced disease stages and poor prognosis, highlighting its potential as a biomarker for early diagnosis and prognostic assessment. Furthermore, targeting PA28γ presents a promising therapeutic approach to impede OSCC progression and enhance treatment efficacy.

While the current evidence underscores PA28γ's significance in oral cancer, further well-designed clinical and experimental studies are needed to validate its utility as a biomarker and therapeutic target. Future research should focus on understanding the molecular mechanisms underlying PA28γ's role in cancer, exploring novel inhibitors, and conducting clinical trials to establish its efficacy in cancer diagnostics and treatment.

By advancing our understanding of PA28γ in oral cancer, we can pave the way for more precise and effective therapeutic strategies, ultimately improving patient outcomes and reducing the burden of this challenging disease.