Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway

Figures & data

Table 1. Clinical characteristics of HCC patients in TCGA database.

	HK2 low level (n = 255)	HK2 high level (n = 116)	P
Gender			0.233
Male	177 (69.4%)	73 (62.9%)
Female	78 (30.6%)	43 (37.1%)
Age			0.370
≤ 61	118 (46.3%)	60 (51.7%)
> 61	137 (53.7%)	56 (48.3%)
Race			0.093
Asian	132 (51.8%)	71(61.2%)
Non Asian	123 (48.2%)	45 (38.8%)
Family History			0.775
HCC	75 (34.1%)	37 (37.0%)
Non	143 (65.9%)	65(63.0%)
Unknown	37(14.5%)	14(12.1%)
Histological Grading			0.245
G1~ G2	168 (65.9%)	69 (59.5%)
G3~ G4	87 (34.1%)	47 (40.5%)
T Stage			0.028
T1~ T2	200 (78.4%)	78 (67.2%)
T3~ T4	55 (21.6%)	38 (32.8%)
Lymph Node Metastasis			0.041
N0	182 (714%)	70 (60.3%)
N+	73 (28.6%)	46 (39.7%)
Distant Metastasis			0.620
M0	185 (72.5%)	81 (69.8%)
M1	70 (27.5%)	35 (30.2%)
Virus Infection			0.000
Yes	122 (47.8%)	31 (26.7%)
No	133 (52.2%)	85 (73.3%)
AFP			0.039
≤400 ng/ml	157 (61.6%)	57 (49.1%)
>400 ng/ml	44 (17.3%)	21 (18.1%)
Not detected	54(21.2%)	38(32.8%)

Table 2. Univariate and multivariate regression analysis were used to evaluate survival related factors.

	Univariate Analysis		Multivariate analysis
	HR (95% CI)	P	HR (95% CI)	P
Gender (female vs male)	0.758 (0.498–1.154)	0.196
Age (>61 vs ≤ 61)	1.027 (1.009–1.045)	0.003	1.026 (1.005–1.047)	0.015
Race (Non Asian vs Asian)	2.042 (1.264–3.298)	0.004	1.297 (0.665–2.532)	0.445
Family History (Yes vs No)	1.795 (1.160–2.778)	0.009	1.403 (0.882–2.232)	0.153
Histological Grading (G3~ G4 vs G1~ G2)	0.955(0.609–1.495)	0.839
T Stage (T3~ T4 vs T1~ T2)	1.806(1.132–2.882)	0.013	1.585 (0.959–2.617)	0.072
Lymph Node Metastasis (N+ vs N0)	1.959(1.274–3.014)	0.002	0.861 (0.475–1.561)	0.623
Distant Metastasis (M1 vs M0)	2.452(1.600–3.759)	0.000	2.298 (1.253–4.215)	0.007
Virus Infection (Yes vs No)	0.567(0.363–0.884)	0.012	1.318 (0.735–2.365)	0.354
AFP (≤400 ng/ml vs > 400 ng/ml)	0.918(0.524–1.607)	0.764
HK2 mRNA level (>273 vs ≤273)	1.566(1.000–2.452)	0.050	1.893 (1.164–3.079)	0.010

Figure 1. Rg3 combined with SFN inhibited cell viability of the HCC cells. (a) molecular structure formula of Rg3. (b-c) cell viability of the HCC cells was determined by MTT assay. **P < 0.01 VS NC group. #P < 0.05 VS SFN or Rg3 group. &P < 0.05 VS SFN+ Rg3 group.

Figure 2. Rg3 combined with SFN declined the glucose consumption and lactate levels of the HCC cells. (a-b) the glucose consumption of the HCC cells. (c-d) THE lactate levels of the HCC cells. *P < 0.05, **P < 0.01 VS NC group. #P < 0.05 VS SFN or Rg3 group. &P < 0.05 VS SFN+ Rg3 group.

Figure 3. HK2 was up-regulated in the HCC patient. (a) the HK2 mRNA levels of the HCC patients. (b) ROC curve analysis of HCC patients. (c-d) TCGA cohort and Kaplan-Meier Plotter analysis was used to draw the overall survival curve.

Figure 4. Rg3 combined with SFN suppressed the PI3K/Akt signaling pathway and HK2 levels. (a-h) the protein expressions of HK2, PI3K, Akt of the HCC cells were detected by western blots. *P < 0.05, **P < 0.01 VS NC group. #P < 0.05, ##P < 0.01, VS SFN or Rg3 group. &P < 0.05, &&P < 0.01 VS SFN+ Rg3 group.