World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Original Article

Volume 14, Number 4, August 2023, pages 285-299

FOS-Like Antigen 1 Expression Was Associated With Survival of Hepatocellular Carcinoma Patients

Figure 1. Immunohistochemical staining of FOSL1 in HCC tumor tissues (× 400) showed weak nuclear expression for FOSL1 (a), moderate nuclear expression (b), strong nuclear expression for FOSL1 (c), weak cytoplasmic expression for FOSL1 (d), moderate cytoplasmic expression (e), and strong cytoplasmic expression for FOSL1 (f). FOSL1: FOS-like antigen 1; HCC: hepatocellular carcinoma.

Figure 2. Immunohistochemical staining of FOSL1 showed strong cytoplasmic expression for FOSL1 in liver cirrhosis (a) (× 100 power magnification), strong cytoplasmic expression for FOSL1 for both liver cirrhosis and HCC (b) (× 100 power magnification), strong cytoplasmic expression for FOSL1 at liver cirrhosis and weak cytoplasmic expression for FOSL1 at HCC (c, d) (× 100 and × 200 power magnification). FOSL1: FOS-like antigen 1; HCC: hepatocellular carcinoma.

Figure 3. Immunohistochemical staining of FOSL1 in HCC (× 400), showed combined weak cytoplasmic and moderate nuclear expression for FOSL1 (a), combined moderate cytoplasmic and strong nuclear expression (b), combined moderate cytoplasmic and weak nuclear expression (c), and combined strong cytoplasmic expression and strong nuclear expression for FOSL1 (d). FOSL1: FOS-like antigen 1; HCC: hepatocellular carcinoma.

Figure 4. Effect of tumor size, histologic grade, FOSL1 expression and tumor recurrence on OS. Kaplan-Meier survival curves for the cumulative (cum) OS according to the log rank test. The OS rate of the HCC patients with tumor size > 5 cm (red line) was significantly lower than that of the patients with tumor size < 5 cm (blue line) (a). The OS rate of the HCC patients with histological grade II and III (red and green lines) were significantly lower than that of the patients with histological grade I (blue line) (b). The OS rate of the HCC patients with strong FOSL1 expression (red line) was significantly lower than that of the patients with moderate or weak FOSL1 expression (green and blue line) (c). The OS rate of the HCC patients with recurrence (red line) and with no recurrence (blue line) (d). FOSL1: FOS-like antigen 1; HCC: hepatocellular carcinoma; OS: overall survival.

**Table 1.** Baseline Demographic, Clinical and Characteristics of the Studied Cohort
Variable	Category	N = 113
TTT: treatment; AFP: alpha-fetoprotein; SD: standard deviation; HCC: hepatocellular carcinoma.
Age/years	Mean ± SD	57.73 ± 7.3
	Median (range)	56 (47 - 74)
Sex	Female	26 (23.1%)
	Male	87 (76.9%)
Hepatitis infection	No	19 (16.8%)
	HBV	7 (6.3%)
	HCV	87 (76.9%)

History of antiviral TTT	No	8 (7.2%)
	Yes	18 (15.9%)
	Unknown	87 (76.9%)
HCC grade	Grade I	20 (17.7%)
	Grade II	45 (39.8%)
	Grade III	48 (42.5%)
AFP (ng/mL)	Mean ± SD	1,505.89 ± 391.3
	Median (range)	116 (9 - 1,886)

Table 1. Baseline Demographic, Clinical and Characteristics of the Studied Cohort

Variable

Variable	Category	N = 113
SD: standard deviation; LVE: lymphovascular embolization.
Tumor size (cm)	Mean ± SD	3.35 ± 1.9
	Median (range)	2.3 (1.5 - 8.2)
Tumor budding	Low	39 (34.5%)
	High	74 (65.5%)
LVE	Positive	72 (63.7%)
Necrosis	Positive	30 (26.5%)
Recurrence	Yes	45 (39.8%)
Mortality	Yes	69 (61.1%)

Correlate	H score (n)		P value	HR (95% CI)	P value
Correlate	Low (n = 58)	High (n = 55)	P value	HR (95% CI)	P value
*P < 0.05. AFP: alpha-fetoprotein; FOSL1: FOS-like antigen 1; LC: liver cirrhosis; HBV: hepatitis B virus; HCV: hepatitis C virus; LVE: lymphovascular embolization; HR: hazard ratio; CI: confidence interval; FOSL1 (C): FOSL1 cytoplasmic expression.
Age/year
< 50 years	10 (15.8%)	14 (22.2%)	0.288	1
> 50 years	48 (84.2%)	41 (77.8%)		0.66 (0.13 - 3.45)	0.619
Sex
Female	10 (15.8%)	16 (27.8%)	0.215	1
Male	48 (84.2%)	39 (72.2%)		0.49 (0.10 - 2.43)	0.381
Tumor size
< 5 cm	45 (78.9%)	39 (27.8%)	0.267	1
> 5 cm	13 (21.1%)	16 (27.8%)		1.44 (0.32 - 6.53)	0.635
AFP
> 200 ng/mL	24 (42.1%)	27 (50%)	0.630	1
< 200 ng/mL	34 (57.9%)	28 (50%)		0.73 (0.20 - 2.66)	0.684
Histological grade
Grade I	15 (26.3%)	5 (9.1%)	0.075	1
Grade II/III	43 (73.7%)	50 (90.9%)		6.07 (1.01 - 8.22)	0.038*
Hepatitis infection
No	6 (10.5%)	2 (3.6%)	0.225	1
HCV/HBV	52 (89.5%)	53 (96.4%)		0.41 (0.07 - 2.59)	0.344
LC
Negative	13 (22.4%)	9 (16.7%)	0.246	1
Positive	45 (77.6%)	46 (83.3%)		1.79 (0.36 - 8.90)	0.479
LVE
Negative	31 (52.6%)	10 (18.2%)	0.022*	1
Positive	27 (47.4%)	45 (81.8%)		5.56 (1.20 - 9.71)	0.028*
Necrosis
Negative	43 (73.7%)	40 (72.2%)	0.605	1
Positive	15 (26.3%)	15 (27.8%)		1.08 (0.25 - 4.60)	0.847
Tumor budding
Low	31 (52.6%)	8 (14.5%)	0.020*	1
High	27 (47.4%)	47 (85.5%)		5.56 (1.20 - 9.71)	0.026*
FOSL1 (C)
Low	38 (65.5%)	11 (20%)	0.001*	1
High	20 (34.5%)	44 (80%)		18.0 (1.96 - 34.9)	0.011*
Recurrence
No	37 (63.2%)	31 (55.6%)	0.235	1
Yes	21 (36.8%)	24 (44.4%)		1.38 (0.37 - 5.19)	0.630
Mortality
Alive	22 (36.8%)	22 (40%)	0.898	1
Dead	36 (63.2%)	33 (60%)		0.92 (0.24 - 3.46)	0.904

Correlate	H score (n)		P value	HR (95% CI)	P value
Correlate	Low (n = 58)	High (n = 55)	P value	HR (95% CI)	P value
*P < 0.05. AFP: alpha-fetoprotein; FOSL1: FOS-like antigen 1; LC: liver cirrhosis; HBV: hepatitis B virus; HCV: hepatitis C virus; LVE: lymphovascular embolization; HR: hazard ratio; CI: confidence interval; FOSL1 (N): FOSL1 nuclear expression.
Age/years
< 50 years	13 (25%)	11 (17.2%)	0.235	1
> 50 years	36 (75%)	53 (82.8%)		2.01 (0.38 - 9.58)	0.415
Sex
Female	10 (18.7%)	16 (25%)	0.517	1
Male	39 (81.3%)	48 (75%)		0.74 (0.15 - 3.69)	0.712
Tumor size
< 5 cm	34 (68.7%)	50 (78.1%)	0.210	1
> 5 cm	15 (31.3%)	14 (21.9%)		0.52 (0.11 - 2.36)	0.395
AFP
> 200 ng/mL	25 (50.1%)	26 (40.6%)	0.460	1
< 200 ng/mL	24 (49.9%)	38 (59.4%)		1.33 (0.36 - 4.93)	0.666
Histological grade
Grade I	10 (18.7%)	10 (15.6%)	0.528	1
Grade II/III	39 (81.3%)	54 (84.4%)		1.39 (0.24 - 7.99)	0.716
Hepatitis infection
No	2 (4.1%)	6 (9.4%)	0.528	1
HCV/HBV	47 (95.9%)	58 (90.6%)		1.39 (0.24 - 7.99)	0.716
LC
Negative	13 (25%)	9 (14.1%)	0.483	1
Positive	36 (75%)	55 (85.9%)		1.42 (0.30 - 6.81)	0.664
LVE
Negative	21(42.6%)	20 (31.2%)	0.174	1
Positive	28 (57.1%)	44 (68.8%)		1.94 (0.50 - 7.64)	0.341
Necrosis
Negative	40 (81.6%)	43 (67.2%)	0.187	1
Positive	9 (18.4%)	21 (32.8%)		2.17 (0.46 - 9.20)	0.328
Tumor budding
Low	22 (43.8%)	17 (26.6%)	0.174	1
High	27 (56.2%)	47 (70.3%)		1.94 (0.50 - 7.64)	0.341
FOSL1 (N)
Low	38 (77.6%)	20 (31.2%)	0.008*	1
High	11 (22.4%)	44 (68.8%)		0.11 (0.02 - 0.61)	0.012*
Recurrence
No	34 (68.8%)	34 (53.1%)	0.253	1
Yes	15 (31.2%)	30 (48.4%)		2.02 (0.51 - 7.80)	0.318
Mortality
Alive	19 (37.5%)	25 (38.1%)	0.267	1
Dead	30 (62.5%)	39 (61.9%)		0.98 (0.26 - 3.73)	0.970

Correlate	H score (N + C)		P value	HR (95% CI)	P value
Correlate	Low (n = 27)	High (n = 86)	P value	HR (95% CI)	P value
*P < 0.05. AFP: alpha-fetoprotein; FOSL1: FOS-like antigen 1; LC: liver cirrhosis; HBV: hepatitis B virus; HCV: hepatitis C virus; LVE: lymphovascular embolization; HR: hazard ratios; CI: confidence interval; N + C: nuclear and cytoplasmic expression.
Age/years
< 50 years	6 (22.2%)	18 (20.9%)	0.771	1
> 50 years	21 (77.8%)	68 (79.1%)		1.31 (0.21 - 8.32)	0.845
Sex
Female	3 (11.1%)	23 (26.7%)	0.379	1
Male	24 (88.9%)	63 (73.3%)		0.38 (0.04 - 3.55)	0.682
Tumor size
< 5 cm	21 (77.8%)	63 (73.3%)	0.806	1
> 5 cm	6 (22.2%)	23 (26.7%)		1.17 (0.96 - 6.89)	0.784
AFP
> 200 ng/mL	12 (44.4%)	39 (45.3%)	0.612	1
< 200 ng/mL	15 (55.6%)	47 (54.7%)		0.92 (0.21 - 4.18)	0.782
Histological grade
Grade I	15 (55.6%)	5 (5.8%)	0.028*	1
Grade II/III	12 (44.4%)	81 (94.2%)		1.73 (0.36 - 8.35)	0.034*
Hepatitis infection
No	6 (22.2%)	2 (2.3%)	0.457	1
HCV/HBV	21 (77.8%)	84 (97.7%)		1.71 (0.26 - 9.41)	0.574
LC
Negative	9 (33.3%)	13 (15.1%)	0.293	1
Positive	18 (66.7%)	73 (84.9%)		2.31 (0.42 - 8.74)	0.237
LVE
Negative	18 (66.7%)	23 (26.7%)	0.023*	1
Positive	9 (33.3%)	63 (73.3%)		6.01 (1.18 - 14.58)	0.031*
Necrosis
Negative	21 (77.8%)	62 (72.1%)	0.537	1
Positive	6 (22.2%)	24 (27.9%)		1.41 (0.24 - 8.24)	0.709
Bile duct proliferation
Mild/moderate	18 (66.7%)	61 (70.9%)	0.546	1
Severe	9 (33.3%)	25 (29.1%)		0.81 (0.16 - 4.01)	0.765
Tumor budding
Low	15 (55.6%)	24 (27.9%)	0.040*	1
High	12 (44.4%)	62 (72.1%)		3.17 (1.05 - 9.72)	0.046*
Recurrence
No	21 (77.8%)	47 (54.7%)	0.186	1
Yes	6 (22.2%)	39 (45.3%)		3.03 (0.53 - 7.25)	0.120
Mortality
Alive	21 (77.8%)	23 (26.7%)	0.034*	1
Dead	6 (22.2%)	64 (73.3%)		1.44 (0.31 - 6.62)	0.035*

Predictor	SR%	P value	HR (95% CI)	P value
*P < 0.05. SR%: survival rate percentages; HR: hazard ratio; 95% CI: 95% confidence intervals for risk of all causes; AFP: alpha-fetoprotein; LC: liver cirrhosis; HBV: hepatitis B virus; HCV: hepatitis C virus; LVE: lymphovascular embolization; FOSL1: FOS-like antigen 1.
Age/years
< 50 years	42.9%	0.313	1
> 50 years	36.7%		1.468 (0.498 - 4.329)	0.428
Sex
Female	62.5%	0.092	1
Male	31%		2.384 (0.707 - 8.034)	0.161
Tumor size
< 5 cm	42.9%	0.034*	1
> 5 cm	22.2%		2.078 (1.041 - 5.138)	0.043*
AFP
> 200 ng/mL	35.3%	0.255	1
< 200 ng/mL	40%		0.889 (0.391 - 2.022)	0.779
Histological grade
Grade I	41.9%	0.041*	1
Grade II/III	16.7%		3.621 (1.077 - 6.118)	0.046*
Hepatitis infection
No	33.3%	0.593	1
HCV/HBV	38.7%		0.730 (0.246 - 2.163)	0.570
LC
Negative	50%	0.230	1
Positive	34.5%		1.394 (0.470 - 4.137)	0.549
LVE
Negative	38.5%	0.613	1
Positive	37.5%		0.871 (0.364 - 2.082)	0.756
Necrosis
Negative	40.7%	0.256	1
Positive	30%		1.335 (0.542 - 3.292)	0.530
Bile duct proliferation
Mild/moderate	42.9%	0.421	1
Severe	34.7%		1.079 (0.648 - 1.798)	0.770
FOSL1
Low	46.8%	0.044*	1
High	33.1%		4.112 (1.057 - 8.091)	0.039*
Recurrence
Negative	59.1%	0.454	1
Positive	66.7%		1.943 (0.412 - 2.160)	0.302