ABSTRACT
Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells‚ decarboxylation of glycolytic intermediate pyruvate to acetyl coenzyme A (acetyl-CoA) in mitochondria. Dihydrolipoyl acetyltransferase (DLAT) is a subunit of the pyruvate dehydrogenase complex. Here‚ we reported that DLAT was commonly increased in lung cancer and its expression was associated with worse clinical outcomes. We found that suppression of DLAT in lung cancer cells resulted in reduced nucleic acid biosynthesis and attenuated cancer cell proliferation through controlling acetylation level of 6-phosphogluconate dehydrogenase (6PGD) ‚ the third enzyme in the oxidative pentose phosphate pathway (PPP) ‚ in which ribulose-5-phosphate (Ru-5-P) is produced for nucleic acid biosynthesis. Together‚ our study contributes to recent interest and discussion cross talk in cancer metabolism‚ which contributes to tumor growth. Future mechanistic studies should lead to the elucidation of the mode of action of DLAT in human lung cancer and establish DLAT as a viable drug target.
ABSTRACT
@#【Objective】To explore the correlation between the expression levels of copper chaperone for superoxide dismutase（CCS）and the malignancy related biomarkers in hepatocellular carcinoma（HCC）.【Methods】From January to December 2018，we obtained fresh samples of surgically dissected HCC paired with para-carcinoma normal tissues from 10 HCC patients and collected their clinical and pathological data. Western blotting（WB）was performed to examine the expression of CCS in HCC tissues and adjacent noncancerous tissues. Immunohistochemical staining（IHC）was employed to detect the expression of Ki67，CD34，vimentin and glypican-3（GPC3）. The correlation between the expression levels of CCS and biomarkers was analyzed by using Wilcoxon rank sum test. The association between CCS expression and clinical pathological characteristics of HCC patients was investigated by using Fisher′s exact probability test.【Results】In 7 of the 10 HCC cases，the expression level of CCS in HCC tissue samples was lower than that in adjacent noncancerous tissues，and in other 3 HCC cases，CCS expression higher. In the group with low CCS expression，compared with those in the group with high CCS expression，the expression levels of Ki67，vimentin and GPC3 were higher （Z=- 2.400，P=0.016；Z=- 2.423，P=0.015；Z=- 2.400，P=0.016），while the expression level of CD34 lower（Z=- 2.423，P=0.015）. There was no statistically significant difference in clinical and pathological variables including gender ，age ，hepatitis B virus infection，liver cirrhosis，preoperative serum AFP level，tumor size，Edmondson-Steiner grade and microvascular invasion between two groups with high and low CCS expression.【Conclusions】The results revealed that in most of HCC patients，the expression level of CCS in HCC tissues was lower than that in adjacent noncancerous tissues. Additionally ， higher expression levels of Ki67，vimentin and GPC3 in HCC tissues with low CCS expression indicated that low expression level of CCS correlated with malignant biological behaviors such as HCC proliferation ，invasion and metastasis. The mechanism that the expression level of CD34 appeared lower in HCC tissues with low CCS expression，however，needs further study. These findings suggest that compared with that in normal liver tissues，CCS expression is decreased in a majority of the cases，and it may serve as a promising therapeutic and prognostic biomarker for HCC.