HIST1H2BK predicts neoadjuvant-chemotherapy response and mediates 5-fluorouracil resistance of gastric cancer cells

Area of Science:

• Oncology
• Proteomics
• Molecular Biology

Background:

• Neoadjuvant chemotherapy (NACT) is standard for advanced gastric cancer (AGC).
• Predicting NACT response in AGC patients remains a clinical challenge.
• Identifying reliable biomarkers for NACT benefit is crucial.

Purpose of the Study:

• To identify plasma protein biomarkers for predicting NACT response in AGC patients.
• To investigate the role of identified biomarkers in 5-Fluorouracil (5-FU) resistance.
• To elucidate the underlying mechanisms of chemoresistance in AGC.

Main Methods:

• Plasma protein screening using mass spectrometry in NACT-sensitive versus NACT-resistant AGC patients (n=6).
• Validation of differential proteins in independent cohorts (ELISA: n=155; Validated: n=203).
• Immunohistochemistry on AGC tissues (n=34) and in vitro/vivo cell-based assays to explore mechanisms.

Main Results:

• Plasma HIST1H2BK was identified as a significant biomarker for NACT response and prognosis in AGC.
• HIST1H2BK was overexpressed in NACT-resistant tissues and promoted 5-FU resistance by inhibiting apoptosis via A2M/LRP/PI3K/Akt pathway.
• Secreted HIST1H2BK from resistant cells conferred resistance to sensitive cells.

Conclusions:

• Plasma protein profiling reveals differences between NACT-resistant and NACT-sensitive AGC patients.
• Plasma HIST1H2BK is a promising biomarker for optimizing NACT in AGC.
• Understanding HIST1H2BK's mechanism provides novel insights into gastric cancer chemoresistance.