P62 accumulation drives colorectal cancer progression by activating NRF2, NF-κB, and mTORC1 pathways.
Background
Colorectal cancer (CRC) is a major global health challenge, often initiated and driven by chronic inflammation. Its progression involves a complex interplay of oncogenic signaling, genetic mutations, and epithelial barrier disruption. Current therapeutic strategies often target late-stage disease, but understanding the early molecular switches that transition from inflammation to tumorigenesis is crucial for prevention. The protein p62, known for its role in autophagy and signaling, has emerged as a key player, but its precise, context-dependent contribution to CRC progression, particularly its dual nature, needed clarification. This review addresses that gap.
Study Design
This comprehensive review synthesized existing literature to elucidate the multifaceted role of the autophagy adaptor and scaffold protein p62 in colorectal cancer (CRC) progression. Researchers analyzed studies detailing p62's involvement in inflammation, cellular signaling, and DNA repair mechanisms across different stages of CRC development. The methodology focused on integrating findings regarding p62's tumor-suppressive functions during early inflammation versus its tumor-promoting activities under conditions of sustained inflammation and accumulation, providing a holistic perspective on its context-dependent actions.
Results
The review revealed that p62 exhibits a critical dual role in colorectal cancer (CRC) progression, acting as both a tumor suppressor and a tumor promoter depending on the inflammatory context and its cellular accumulation.
During early stages of inflammation, p62 exerts tumor-suppressive functions by facilitating the clearance of inflammasomes, activating the
NRF2pathway, and downregulating pro-inflammatory cytokines, thereby mitigating the inflammatory environment. However, under conditions of sustained inflammation, p62 accumulates, shifting its role towards promoting tumorigenesis. This accumulation reinforces the activation of key oncogenic pathways, includingNRF2,NF-κB, andmTORC1, through positive feedback loops. Furthermore, excessive p62 was found to impair DNA double-strand break repair mechanisms, which in turn facilitates the accumulation of oncogenic mutations, directly contributing to cancer development and progression.
Key Findings
- P62 initially suppresses inflammation in early colorectal cancer by clearing inflammasomes and activating
NRF2. - Sustained inflammation leads to p62 accumulation, shifting its role to promote tumorigenesis.
- Accumulated p62 reinforces
NRF2,NF-κB, andmTORC1pathway activation via positive feedback loops. - Excessive p62 impairs DNA double-strand break repair, facilitating oncogenic mutations.
- Enhancing autophagic clearance of p62 is proposed as a therapeutic strategy for inflammation-associated CRC.
Why It Matters
This review fundamentally redefines our understanding of p62's role in colorectal cancer, highlighting its context-dependent functions. The identification of p62 accumulation as a critical switch from anti-inflammatory to pro-tumorigenic suggests novel therapeutic avenues. For clinicians and researchers, this implies that strategies aimed at enhancing the autophagic clearance of p62 could represent a promising approach to prevent inflammation-associated CRC or to intervene in early-stage disease. This insight could guide the development of new drugs or repurposing existing compounds that modulate autophagy, potentially offering a more targeted and effective strategy for CRC prevention and treatment by disrupting these identified positive feedback loops.
colorectal cancer
p62
autophagy
inflammation
nrf2
nf-kb