Expression and Significance of PI3K p85α and p53 Protein in Colorectal Cancer: A Comprehensive Analysis
Introduction
Colorectal cancer (CRC) is a significant global health concern, ranking as the third most common malignancy worldwide. It accounts for approximately 10% of all new cancer cases and 9.4% of cancer-related deaths annually, making it the second leading cause of cancer mortality. Despite advancements in early screening and therapeutic strategies, the incidence of CRC remains high, and survival outcomes for many patients are suboptimal. Therefore, identifying novel biomarkers is crucial for improving early detection, prognostic assessment, and clinical management of CRC.
The development and progression of CRC involve a multistep process driven by multiple genetic and environmental factors, including alterations in genes such as TP53. The wild-type TP53 gene encodes p53, a nuclear tumor suppressor protein that plays a critical role in inhibiting tumor growth and preventing malignant transformation. Under normal conditions, p53 is maintained at low intracellular levels through continuous proteasomal degradation mediated by the E3 ubiquitin ligase MDM2, its primary negative regulator. Following TP53 mutation, the resulting p53 protein often acquires an extended half-life and increased stability, leading to its abnormal accumulation within the nucleus. Such mutations typically abrogate the tumor-suppressive functions of p53 and may even confer oncogenic gain-of-function properties. TP53 mutation is one of the most frequent genetic alterations in human cancers and is regarded as a key driver event in the development of multiple tumor types.
Phosphatidylinositol 3-kinase (PI3K) is a specialized class of lipid kinases that phosphorylates phosphatidylinositol lipids, thereby propagating intracellular signaling cascades. PI3K plays a critical role in regulating diverse cellular processes, including cell proliferation, differentiation, apoptosis, and intercellular adhesion. Protein kinase B (AKT) serves as a crucial downstream effector of PI3K signaling. The PI3K/AKT pathway participates in cellular malignant transformation processes and promotes tumor cell proliferation, invasion, and metastasis. Aberrant activation of PI3K/AKT constitutes a key mechanism regulating multidrug resistance, with PI3K recognized as a significant contributor to chemotherapy resistance in cancer treatment. As an upstream signaling molecule in the PI3K/AKT pathway, PI3K consists of a p85 regulatory subunit and a p110 catalytic subunit. The p85 regulatory subunit is essential for stabilizing the p110 catalytic subunit, facilitating its recruitment, and activating PI3K. Among PI3K family members, p85α represents the most abundantly expressed regulatory subunit. In addition to modulating PI3K activity through its interaction with p110, p85α itself also exerts important biological functions in CRC cell proliferation. Previous studies have shown that targeted silencing of PI3K p85α via RNA interference can effectively inhibit cell proliferation, induce G1-phase cell-cycle arrest, and enhance the sensitivity of CRC cells to 5-fluorouracil-induced apoptosis. However, the differential expression patterns of PI3K p85α during colorectal carcinogenesis and progression remain poorly understood. Moreover, studies examining the potential correlation between PI3K p85α and p53 expression in CRC tissues, as well as their clinical prognostic significance, are limited.
Materials and Methods
The study included paraffin-embedded tissue specimens of CRC and paracancerous intestinal mucosa, surgically resected from two medical centers between December 2014 and August 2024. Immunohistochemistry was employed to assess the expression of PI3K p85α and p53 proteins in CRC tissues and corresponding paracancerous intestinal mucosa. The expression patterns were analyzed, and associations with clinicopathological features of CRC patients were examined. The potential roles of PI3K p85α and p53 in CRC pathogenesis and progression, as well as their relationships with patient prognosis, were explored.
Results
PI3K p85α protein expression was significantly higher in CRC tissues than in paracancerous intestinal mucosa, with a positivity rate of 80.2% in CRC tissues compared to 17.6% in paracancerous mucosa. This suggests that PI3K p85α expression is upregulated during colorectal carcinogenesis and may play a role in the early prediction of malignant transformation. p53 protein expression was significantly higher in CRC tissues (62.9%) compared to normal mucosa (0%). This indicates that upregulation of p53 expression is associated with the progression from normal colorectal mucosa to carcinoma.
PI3K p85α protein expression showed a significant correlation with clinical stage in CRC patients, while p53 protein expression was significantly associated with lymph node metastasis. No statistically significant correlation was observed between PI3K p85α and p53 protein expression in CRC tissue.
Univariate and multivariate survival analyses revealed that clinical stage, tumor differentiation degree, and PI3K p85α protein expression were independent prognostic factors for CRC patients.
Discussion
This study highlights the importance of PI3K p85α and p53 in CRC pathogenesis and progression. The upregulation of PI3K p85α expression during colorectal carcinogenesis suggests its potential as an early indicator of malignant transformation. The significant association between p53 expression and lymph node metastasis indicates its role in the progression of CRC. Further studies are needed to elucidate the underlying molecular mechanisms and validate the prognostic value of these biomarkers in larger, multi-center cohorts.
