Introduction

Cancer is one of the leading causes of mortality worldwide. According to a 2020 report by GLOBOCAN, there were approximately 10.3 million deaths due to cancer and around 19.3 million new annual cases globally. Among these, oral cancer is particularly significant in India, where around 77,000 new cases and 52,000 deaths due to cancer are recorded annually. Notably, oral cancer, a subset of head and neck cancer, is prevalent and shows an increasing frequency, particularly oral squamous cell carcinoma (OSCC), which accounts for 95% of head and neck cancer cases. The prognosis for oral cancer is often poor due to delayed detection and lack of effective early biomarkers. Understanding the molecular and signaling pathways involved in oral cancer is essential for developing new diagnostics and therapeutics. This article discusses significant pathways involved in the progression of oral cancer, including PI3K/AKT/mTOR, NF-κB, Wnt, Notch, MAPK, Hippo, and Hedgehog pathways.

Fig. 1 Role of PI3K signaling cascade in cancers (Kumari M., et al. 2024).

Key Pathways Involved in Oral Cancer

PI3K/AKT/mTOR Signaling

The PI3K/AKT/mTOR signaling pathway is crucial for cellular growth, motility, survival, metabolism, and angiogenesis. This pathway's dysregulation is linked to the development and progression of various cancers, including head and neck cancers (HNC). PI3K is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), leading to AKT activation via phosphorylation. Activated AKT impacts multiple downstream targets, including mTOR, promoting protein synthesis and inhibiting autophagy. Aberrations in this pathway, such as PTEN inhibition, significantly contribute to cancer development.

Studies have shown that inhibitors targeting this pathway, such as oridonin and various PI3K inhibitors (e.g., PI-103, PI-828, PX-866), exhibit anti-cancer activities by inhibiting cell proliferation, inducing apoptosis, and arresting the cell cycle in oral cancer cell lines. These findings validate the critical role that the PI3K/AKT/mTOR pathway plays in oral cancer progression.

NF-κB Pathway

The NF-κB signaling pathway is pivotal in cellular survival, immune responses, inflammation, cancer progression, and chemoresistance. Normally sequestered in the cytoplasm by inhibitory protein (IkB), NF-κB is released upon IkB phosphorylation, allowing it to enter the nucleus and regulate gene expression. NF-κB controls genes involved in cell proliferation, angiogenesis, and survival in cancer cells, such as Bcl2, VEGF, and COX-2.

Studies have revealed that NF-κB's increased expression in oral cancer promotes inflammation and cell survival, while its inhibition reduces tumor growth and viability. For instance, the downregulation of NF-κB by curcumin demonstrated decreased viability of HPV16 positive oral cancer cells, signifying NF-κB's role in promoting oral carcinogenesis.

Wnt Signaling Pathway

The Wnt signaling pathway is integral to stem cell renewal, differentiation, and proliferation. Dysregulation of Wnt signaling is linked to poor prognosis in oral squamous cell carcinoma (OSCC). Wnt activates intracellular signaling cascades, leading to gene transcription involved in cell proliferation and survival. There are two types of Wnt pathways: canonical (β-catenin-dependent) and non-canonical (β-catenin-independent).

Several Wnt genes, such as Wnt5a and Fzd5, are upregulated in oral cancer and contribute to tumor invasiveness and migration. Studies have shown that targeting the Wnt pathway (e.g., through porcupine and CBP/β-catenin inhibitors) can reduce oral cancer cell viability and induce apoptosis, making the Wnt pathway a potential therapeutic target.

Notch Signaling Pathway

Notch signaling is a highly conserved cell-to-cell communication pathway involved in cell fate determination and growth. While Notch is active in some cancers, its role in oral cancer shows a suppression pattern, especially in squamous cell carcinoma (SCC). Four Notch receptors (Notch 1-4) and two types of ligands (Jagged and Delta-like) interact to activate downstream gene transcription.

Research has demonstrated that Notch signaling influences epithelial-mesenchymal transition (EMT) and metastasis in OSCC. Inhibiting Notch signaling with γ-secretase inhibitors, such as DAPT, has shown reduced migration potential in OSCC cells. This pathway thus offers possible therapeutic interventions for controlling oral cancer progression.

MAPK/ERK Signaling Pathway

The MAPK/ERK signaling pathway regulates apoptosis, cellular proliferation, angiogenesis, differentiation, metastasis, and invasion. MAPK signaling consists of four main pathways: JNK, ERK1/2, ERK5, and p38, which modulate gene expression by transducing extracellular signals to the nucleus.

Studies have indicated that various components of the MAPK/ERK pathway are involved in promoting tumor cell proliferation and inhibiting apoptosis in oral cancer. For example, S100A7 activation modulates the MAPK pathway in OSCC, affecting tumor cell growth and migration. Targeting these pathways could help control tumor growth and metastasis.

Hippo Signaling Pathway

The Hippo signaling pathway regulates organ size, tissue growth, and stem cell attributes by controlling cellular contacts, apoptosis, and proliferation. Dysregulation in this pathway can contribute to tumorigenesis. Core components include LATS kinases, MOB1, MST kinases, and SAV1, which inhibit tumorigenic processes through downstream effectors YAP and TAZ.

Research in tongue squamous cell carcinoma (TSCC) has shown that TAZ, a downstream effector, promotes cell proliferation, migration, invasion, and chemoresistance. Targeting components of the Hippo pathway could provide novel approaches for oral cancer therapeutics.

Hedgehog Signaling Pathway

The Hedgehog (HH) signaling pathway is essential for embryonic development and adult stem cell function. This pathway involves ligands SHH, IHH, and DHH, and transcription factors GLI1, GLI2, and GLI3. Dysregulation can lead to various cancers, including OSCC.

Studies have highlighted the role of HH signaling in the tumor microenvironment and its potential as an independent prognostic factor in OSCC. Targeting the HH pathway might improve survival rates and treatment outcomes for patients with oral cancer.

Conclusion

Understanding the underlying molecular and cellular pathways involved in oral cancer is crucial for developing effective therapeutic strategies. The PI3K/AKT/mTOR, NF-κB, Wnt, Notch, MAPK, Hippo, and Hedgehog pathways play pivotal roles in oral cancer, with components often overexpressed or activated in oral cancers. Targeting these pathways can inhibit tumor growth and metastasis.

Future research should focus on elucidating these pathways' intricacies, discovering new therapeutic targets, and developing inhibitors to improve oral cancer treatment outcomes, Understanding these pathways will provide insights into better management strategies for oral cancer patients, ensuring improved prognosis and survival rates.