Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease

doi:10.4254/wjh.v16.i1.75

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World Journal of Hepatology

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Basic Study

World J Hepatol. Jan 27, 2024; 16(1): 75-90
Published online Jan 27, 2024. doi: 10.4254/wjh.v16.i1.75

Table 1 Gene expression of markers related to hepatocarcinogenesis

Variables¹	Control (n = 8)	HCC (n = 7)	RIF (n = 7)	P value
Tuba1c	1.28 (0.18-2.76)	4.27 (0.00-9.69)	1.38 (0.29-19.8)	0.839
Aldob	2.46 (0.01-5.78)	4.24 (0.00-9.92)	0.12 (0.00-2.69)	0.595
Afp	1.28 (0.18-2.76)	2.33 (0.00-9.69)	1.38 (0.29-19.8)	0.837
Mmp2	1.81 (0.03-5.15)	31.4 (0.25-62.2)	0.92 (0.16-18.4)	0.101
Mmp9	2.36 (0.02-4.25)^a	23.6 (2.69-76.8)^b	14.6 (1.32-28.7)^a^,^b	0.035
miR-122	1.14 (0.34-2.34)^a	7.07 (1.41-11.8)^b	2.62 (1.20-6.00)^a^,^b	0.005
miR-34a	0.94 (0.63-1.70)^b	0.39 (0.33-0.44)^a	0.33 (0.13-0.89)^a	0.007
miR-26b	1.04 (0.61-1.57)^a^,^b	0.36 (0.21-1.85)^a	2.22 (1.46-2.96)^b	0.026
miR-224	1.05 (0.41-2.45)^a^,^b	2.97 (1.96-5.94)^b	0.58 (0.13-0.85)^a	0.005
miR-33a	0.98 (0.53 – 2.16)	0.60 (0.54-1.17)	1.4 (0.70-1.60)	0.445
miR-143	1.18 (0.25-3.67)	1.40 (0.54-5.16)	0.62 (0.17-2.54)	0.471
miR-155	1.46 (0.32-1.96)	0.63 (0.01-1.18)	0.34 (0.04-1.46)	0.074
miR-375	0.79 (0.61-2.42)	0.85 (0.17-1.09)	0.38 (0.14-1.76)	0.216
miR-21	1.12 (0.34-2.13)	1.49 (0.91-6.08)	1.69 (0.84-3.68)	0.188

¹Variables expressed by median (25^th–75^th percentiles).

^aP < 0.05. Different letters indicate a significant difference between groups.

^bP < 0.05. Different letters indicate a significant difference between groups.

HCC: Hepatocellular carcinoma; RIF: Rifaximin; Afp: Alpha-fetoprotein; Aldo-B: Aldolase-B; Mmp: Metalloproteinases; Tuba1c: Tubulin alpha-1c.

Table 2 Correlations between hepatocarcinogenesis, autophagy and epigenetic markers

Variables¹		microRNAs			Hepatocarcinogenesis					Autophagy and Epigenetic
Variables¹		miR-26b	miR-224	miR-34a	*Mmp2*	*Mmp9*	*Afp*	*Tuba1c*	*Aldob*	*Becn1*	*p62/Sqstm1*	*Map1lc3b*	*Ezh2*	*Carm1*	p62 protein	MAP1LC3B protein
microRNAs	miR-122	-0.235	0.075	0.400^a	0.195	0.422	-0.189	0.085	0.030	-0.502^a	-0.673^b	-0.554^a	-0.760^b	-0.375	-0.245	0.017
	miR-26b		-0.360	0.538^a	-0.071	0.203	0.199	-0.090	-0.113	-0.089	0.164	-0.047	-0.005	0.525^a	-0.124	0.186
	miR-224			-0.195	0.041	-0.241	-0.201	0.025	0.153	-0.298	-0.022	0.032	-0.061	-0.335	-0.007	-0.393
	miR-34a				0.110	0.426	0.123	0.110	-0.127	-0.461^a	-0.340	-0.612^b	-0.584^b	0.181	-0.400	-0.191
Hepatocarcinogenesis	Mmp2					0.742^b	0.704^b	0.957^b	0.548^b	-0.321	-0.133	-0.321	-0.361	-0.286	-0.318	-0.368
	Mmp9						0.521^a	0.703^b	0.292	-0.398	-0.276	-0.351	-0.586^b	-0.278	-0.547^a	-0.229
	Afp							0.702^b	0.468^a	-0.086	0.049	-0.173	0.038	-0.073	-0.328	-0.078
	Tuba1c								0.644^b	-0.324	-0.058	-0.281	-0.350	-0.282	-0.258	-0.246
	Aldob									-0.137	-0.042	0.186	0.111	-0.314	-0.032	0.174
Autophagy and Epigenetic	Becn1										0.541^b	0.771^b	0.597^b	0.433	0.631^b	0.302
	p62/Sqstm1											0.657^b	0.609^b	0.459	0.554^a	0.265
	Map1lc3b												0.718^b	0.230	0.512^a	0.343
	Ezh2													0.288	0.342	0.253
	Carm1														0.185	-0.044
	p62 protein															0.406

¹Variables were evaluated by Spearman's r correlation coefficient: Moderate (0.3 < r < 0.6), strong (0.6 < r < 0.9) or very strong (0.9 < r < 1.0).

^aP < 0.05, correlation significant at the 0.05 level.

^bP < 0.01, correlation significant at the 0.01 level.

Afp: Alpha-fetoprotein; Aldo-B: Aldolase-B; Becn-1: Beclin-1; Carm1: Coactivator associated arginine methyltransferase-1; Ezh-2: Enhancer of zeste homolog-2; Map1lc3b: Autophagy-related factor LC3A/B; Mmp: Metalloproteinases; p62/Sqstm1: P62/sequestosome-1; Tuba1c: Tubulin alpha-1c.

Table 3 Distribution of liver histopathological findings according to general non-alcoholic fatty liver disease scoring system for rodent models, n (%)

Variable¹	Control (n = 8)	HCC (n = 7)	RIF (n = 7)
No MASLD	8 (100)	0 (0.0)	0 (0.0)
MASLD	0 (0.0)	0 (0.0)	0 (0.0)
MASH	0 (0.0)	7 (100)	7 (100)

¹Variables described as frequency (%).

HCC: Hepatocellular carcinoma; MASLD: Metabolic-dysfunction associated steatotic liver disease; MASH: Metabolic-dysfunction associated steatohepatitis; RIF: Rifaximin.

Table 4 Comparison between animals in the rifaximin-group that developed or not hepatocellular carcinoma

Variables¹	Developed HCC (n = 4), median (min–max)	Did not developed HCC (n = 3), median (min–max)	P value
miR-122	2.27 (1.20–4.57)	2.97 (1.51–5.98)	0.571
miR-375	0.42 (0.14–1.76)	0.33 (0.30–0.67)	1.000
miR-26b	1.97 (1.10–3.38)	2.41 (1.97–3.99)	0.571
miR-224	0.46 (0.13–0.85)	0.58 (0.46–0.82)	0.857
miR-34	11.0 (7.17–18.9)	10.0 (8.64–10.5)	0.786
miR-21	2.36 (0.84–3.68)	1.68 (1.00–1.69)	0.700
miR-143	0.76 (0.17–2.53)	0.48 (0.25–1.96)	1.000
miR-155	0.69 (0.06–1.46)	0.13 (0.03–0.36)	0.250
miR-33a	0.88 (0.52–1.86)	1.55 (1.40–1.58)	0.400
Mm2	7.95 (0.58–18.4)	0.71 (0.16–0.92)	0.229
Mm9	24.0 (1.32–28.7)	8.48 (1.73–14.6)	0.400
Afp	6.99 (1.38–19.8)	0.46 (0.29–0.48)	0.057
Tuba1c	4.63 (0.30–7.12)	0.26 (0.25–0.30)	0.057
Aldob	2.32 (0.11–2.69)	0.07 (0.00–0.12)	0.114
Becn1	0.70 (0.67–0.85)	0.74 (0.66–0.76)	1.000
p62/Sqstm1	0.84 (0.54–0.98)	0.72 (0.64–0.79)	0.629
Map1lc3b	0.24 (0.22–0.35)	0.27 (0.21–0.29)	1.000
Ezh2	29.0 (28.0–30.1)	27.5 (27.2–28.0)	0.114
Carm1	0.79 (0.77–1.67)	1.23 (1.08–1.68)	0.400
p62/SQSTM1 protein	1.07 (0.16–2.89)	1.78 (1.19–2.36)	0.355
MAP1LC3B protein	2.00 (0.87–4.78)	2.20 (0.86–3.57)	0.643

¹Variables expressed by median (25^th–75^th percentiles).

P < 0.05 is considered significant.

Aldob: Aldolase B; Afp: Alpha-fetoprotein; Becn-1: Beclin-1; Carm1: Coactivator associated arginine methyltransferase-1; Ezh-2: Enhancer of zeste homolog-2; HCC: Hepatocellular carcinoma; Map1lc3b: Autophagy-related factor LC3A/B; Mmp: Metalloproteinases; p62/Sqstm1: P62/sequestosome-1; RIF: Rifaximin; Tuba1c: Tubulin alpha 1c.

Table 5 Comparison between the animals that developed and did not develop hepatocellular carcinoma

Variables¹	HCC (n = 11), median (min–max)	No HCC (n = 11), median (min–max)	P value
miR-122	4.49 (1.20–11.8)	1.41 (0.34–5.98)	0.029^a
miR-375	0.64 (0.14–1.76)	0.72 (0.30–2.42)	0.512
miR-26b	1.10 (0.46–3.38)	1.23 (0.59–3.99)	0.656
miR-224	1.40 (0.13–5.94)	0.82 (0.41–2.45)	0.545
miR-34a	7.73 (2.29–18.9)	1.79 (0.14–10.5)	0.012^a
miR-21	1.92 (0.84–6.08)	1.46 (0.34–2.13)	0.109
miR-143	1.08 (0.17–5.16)	1.13 (0.25–3.67)	0.756
miR-155	0.66 (0.01–1.46)	0.60 (0.03–1.95)	0.349
miR-33a	0.66 (0.52–1.86)	1.40 (0.34–2.64)	0.200
Mm2	18.4 (0.25–62.2)	1.17 (0.03–5.15)	0.017^a
Mm9	23.6 (1.32–76.8)	2.76 (0.02–14.6)	0.013^a
Afp	3.23 (0.00–19.8)	0.62 (0.18–2.76)	0.190
Tuba1c	7.12 (0.12–27.8)	0.76 (0.12–3.71)	0.017^a
Aldob	2.32 (0.00–9.92)	1.35 (0.00–5.78)	0.549
Becn1	0.68 (0.44–0.87)	0.88 (0.66–1.39)	0.004^a
p62/Sqstm1	0.65 (0.32–1.06)	0.92 (0.59–1.31)	0.052
Map1lc3b	0.25 (0.19–0.37)	0.86 (0.21–1.53)	0.004^a
Ezh2	28.4 (25.8–30.1)	30.2 (27.2–31.8)	0.010^a
Carm1	0.69 (0.37–1.67)	1.10 (0.56–1.68)	0.026^a
p62/SQSTM1 protein	1.27 (0.16–2.39)	2.87 (1.19–9.12)	0.013^a
MAP1LC3B protein	1.29 (0.57–4.78)	2.10 (0.86–5.05)	0.183

¹Variables expressed by median (25^th–75^th percentiles).

^aP < 0.05 is considered significant.

Aldob: Aldolase B; Afp: Alpha-fetoprotein; Becn-1: Beclin-1; Carm1: Coactivator associated arginine methyltransferase-1; Ezh-2: Enhancer of zeste homolog-2; HCC: Hepatocellular carcinoma; Map1lc3b: Autophagy-related factor LC3A/B; Mmp: Metalloproteinases; p62/Sqstm1: P62/sequestosome-1; RIF: Rifaximin; Tuba1c: Tubulin alpha 1c.

Citation: Michalczuk MT, Longo L, Keingeski MB, Basso BS, Guerreiro GTS, Ferrari JT, Vargas JE, Oliveira CP, Uribe-Cruz C, Cerski CTS, Filippi-Chiela E, Álvares-da-Silva MR. Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease. World J Hepatol 2024; 16(1): 75-90
URL: https://www.wjgnet.com/1948-5182/full/v16/i1/75.htm
DOI: https://dx.doi.org/10.4254/wjh.v16.i1.75