KRT13 Drives Pancreatic Cancer Malignancy Via the PI3K/AKT-PPARG Axis While Enhancing Sensitivity to Navitoclax.

Background

Pancreatic cancer remains one of the most aggressive malignancies, characterized by late diagnosis, limited treatment options, and a dismal prognosis, with a 5-year survival rate consistently below 13%. The molecular mechanisms driving its progression are incompletely understood, highlighting the need to identify novel regulators of oncogenic pathways. This study focused on keratin 13 (KRT13), a cytoskeletal protein, and investigated its role in pancreatic cancer pathogenesis, particularly its regulatory effect on peroxisome proliferator-activated receptor gamma (PPARG) through the PI3K/AKT signaling axis. MATERIAL AND

Methods

We integrated in vitro cellular assays with molecular biology approaches and bioinformatic analyses to systematically examine KRT13 expression and function. Pancreatic cancer cell lines were used for functional studies, including proliferation, migration, and pathway modulation experiments. Gene expression levels were assessed via quantitative PCR. Expression of KRT13 was further validated via immunohistochemistry on tissue sections from 85 patients. Public transcriptomic datasets (eg, TCGA) were interrogated to evaluate clinical correlations. Mechanistic insights were gained through pharmacological inhibition and genetic silencing of key pathway components. Further in vitro investigation of drug sensitivity was performed with patient-derived organoids (PDOs).

Results

KRT13 expression was markedly upregulated in pancreatic tumor tissues compared to adjacent normal samples. This result was also confirmed in a set of 85 clinical samples, showing a strong positive correlation with PPARG levels. Clinically, elevated KRT13 was significantly associated with reduced overall survival (log-rank P<0.001). Importantly, analysis of The Cancer Genome Atlas (TCGA) database revealed that KRT13 expression was significantly associated with tumor TNM stage and other clinical parameters. Functional experiments demonstrated that KRT13 activates the PI3K/AKT signaling cascade, leading to subsequent upregulation of PPARG. This activation promoted pancreatic cancer cell proliferation and migration, effects that were attenuated upon PI3K/AKT pathway inhibition. Drug sensitivity assays using patient-derived organoids (PDOs) demonstrated that KRT13 significantly enhanced the sensitivity of pancreatic cancer to Navitoclax.

Conclusions

Our findings establish KRT13 as a critical contributor to pancreatic cancer progression, via the PI3K/AKT-PPARG regulatory axis. These results underscore the potential of KRT13 as a prognostic biomarker and a candidate therapeutic target, offering new insights into the molecular pathogenesis of this lethal disease.