TY - JOUR
T1 - Association between individual Warburg-related proteins and prognosis in colorectal cancer
AU - Offermans, Kelly
AU - Jenniskens, Josien C. A.
AU - Simons, Colinda C. J. M.
AU - Samarska, Iryna
AU - Fazzi, Gregorio E.
AU - Smits, Kim M.
AU - Schouten, Leo J.
AU - Weijenberg, Matty P.
AU - Grabsch, Heike
AU - van den Brandt, Piet A.
PY - 2025/3/1
Y1 - 2025/3/1
N2 - We previously showed that Warburg subtyping (low/moderate/high), based on the expression of six glycolytic proteins and transcriptional regulators [glucose transporter 1 (GLUT1), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), monocarboxylate transporter 4 (MCT4), p53, and PTEN], holds independent prognostic value in colorectal cancer (CRC) patients. The present study aimed to investigate whether the expression level of one of the proteins (GLUT1, PKM2, LDHA, MCT4, p53, and PTEN) can act as a proxy for our previously identified six protein-based Warburg subtypes. Protein expression levels for individual Warburg-related proteins were available for 2,251 CRC patients from the Netherlands Cohort Study. Kaplan-Meier curves and Cox regression were used to explore associations between individual Warburg-related proteins and CRC-specific and overall survival. Previously identified associations between Warburg subtypes and CRC-specific and overall survival were adjusted for individual proteins, showing a significant association with survival in the current study. Multivariable-adjusted analyses showed that the expression of GLUT1, LDHA, MCT4, PKM2, or p53 was associated with neither CRC-specific nor overall survival. Decreasing PTEN expression was associated with significantly poorer overall survival (p-trend(categories) = 0.026). Additional adjustment for PTEN expression had minimal impact on the previously identified association between Warburg subtypes and survival, and the six protein-based Warburg-high subtype remained a statistically significant predictor of overall survival (hazard ratio 1.15; 95% CI 1.01-1.32). In conclusion, our results emphasise that individual Warburg-related proteins cannot serve as a proxy or surrogate marker for Warburg subtyping, thereby highlighting the importance of combining the expression levels of multiple Warburg-related proteins when examining the prognostic significance of a complex biological pathway such as the Warburg effect.
AB - We previously showed that Warburg subtyping (low/moderate/high), based on the expression of six glycolytic proteins and transcriptional regulators [glucose transporter 1 (GLUT1), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), monocarboxylate transporter 4 (MCT4), p53, and PTEN], holds independent prognostic value in colorectal cancer (CRC) patients. The present study aimed to investigate whether the expression level of one of the proteins (GLUT1, PKM2, LDHA, MCT4, p53, and PTEN) can act as a proxy for our previously identified six protein-based Warburg subtypes. Protein expression levels for individual Warburg-related proteins were available for 2,251 CRC patients from the Netherlands Cohort Study. Kaplan-Meier curves and Cox regression were used to explore associations between individual Warburg-related proteins and CRC-specific and overall survival. Previously identified associations between Warburg subtypes and CRC-specific and overall survival were adjusted for individual proteins, showing a significant association with survival in the current study. Multivariable-adjusted analyses showed that the expression of GLUT1, LDHA, MCT4, PKM2, or p53 was associated with neither CRC-specific nor overall survival. Decreasing PTEN expression was associated with significantly poorer overall survival (p-trend(categories) = 0.026). Additional adjustment for PTEN expression had minimal impact on the previously identified association between Warburg subtypes and survival, and the six protein-based Warburg-high subtype remained a statistically significant predictor of overall survival (hazard ratio 1.15; 95% CI 1.01-1.32). In conclusion, our results emphasise that individual Warburg-related proteins cannot serve as a proxy or surrogate marker for Warburg subtyping, thereby highlighting the importance of combining the expression levels of multiple Warburg-related proteins when examining the prognostic significance of a complex biological pathway such as the Warburg effect.
KW - Warburg effect
KW - survival
KW - prognosis
KW - colorectal cancer
KW - glycolysis
KW - TUMOR ANGIOGENESIS
KW - COLON-CANCER
KW - EXPRESSION
KW - GROWTH
KW - P53
KW - GLYCOLYSIS
KW - METABOLISM
KW - GLUT1
KW - VALIDATION
KW - HALLMARKS
U2 - 10.1002/2056-4538.70016
DO - 10.1002/2056-4538.70016
M3 - Article
SN - 2056-4538
VL - 11
JO - Journal of Pathology Clinical Research
JF - Journal of Pathology Clinical Research
IS - 2
M1 - e70016
ER -