Aldo‐keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time‐resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha‐fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66;
P
< 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early‐stage HCC and AFP‐negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation.
Conclusion
: AKR1B10 is a potent serum marker for detection of HCC and early‐stage HCC, with better diagnostic performance than AFP.
Neutral sphingomyelinase 1 (NSMase1) mediates caspase-3 activation and apoptosis. However, the role of NSMase1, especially exosome-borne NSMase1 in hepatocellular carcinoma (HCC), remains unclear. We report that NSMase1, which converts sphingomyelin (SM) to ceramide, was significantly downregulated in HCC tissues. Low NSMase1 expression predicted poor long-term survival of HCC patients. NSMase1 downregulation in HCC resulted in increased SM and reduced ceramide (Cer) that led to an increased SM/Cer ratio. Interestingly, NSMase1 and NSMase activity were also decreased in exosomes isolated from HCC tissues and cell lines. Furthermore, NSMase activity increased in exosomes isolated from the culture medium of L02 cells transfected with pEGFP-C3-NSMase1 (NSMase1-Exo). NSMase1-Exo suppressed HCC cell growth and induced apoptosis via reduction of the SM/Cer ratio. Thus, NSMase1 in exosomes inhibits HCC growth by decreasing the SM/Cer ratio.
Rhodium (II) complex with 2-benzoylpyridine (Rh(L)Cl) is a new, synthetic, active metal-complex, which is produced by the reaction of 2-benzoylpyridine (L) with rhodium chloride hydrate (RhCl·nHO). The crystal structure was determined by X-ray diffraction which is mono-nuclear. In order to explore the biological properties of the novel complex, a series of studies were performed. The results showed that Rh(L)Cl had the anti-tumor activity in HepG and other cell lines and has been shown to induce G1 cell cycle arrest and apoptosis in HepG cells. The anti-cancer effect of Rh(L)Cl is regulated by increased expression of caspase-3 and PARP via the mitochondrial and the death receptor pathways. Bcl-2 family proteins might play an important role in the Rh(L)Cl-induced changes in these two pathways. Further studies indicated that Rh(L)Cl increased the level of reactive oxygen species (ROS), but that Rh(L)Cl-induced apoptosis was ROS-independent. In conclusion, Rh(L)Cl is a potential new anti-tumor drug, which induces HepG cell death via the mitochondrial and death receptor pathways and has no obvious toxicity to normal liver cell.
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