PLASMA EXPRESSION LEVELS OF MICRORNA-21 MIGHT HELP IN THE DETECTION OF HCV PATIENTS COMPLICATED BY HEPATOCELLULAR CARCINOMA

EL-HAMMADY, Amr M; MAREI, Yasmin M; MOHAMMED, Raafat R; RAHMAN, Shaymaa M Abd El; MAREI, Yomna M; SARHAN, Rizk S

doi:10.1590/S0004-2803.24612024-025

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ORIGINAL ARTICLE/HEPATOLOGY • Arq. Gastroenterol. 61 • 2024 • https://doi.org/10.1590/S0004-2803.24612024-025 linkcopy

PLASMA EXPRESSION LEVELS OF MICRORNA-21 MIGHT HELP IN THE DETECTION OF HCV PATIENTS COMPLICATED BY HEPATOCELLULAR CARCINOMA

Os níveis de expressão plasmática de microRNA-21 podem ajudar na detecção de pacientes com HCV complicados por carcinoma hepatocelular

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective: To investigate the ability of the estimated plasma gene-expression levels of microRNA (miR)-21 and 126 to define patients suspected to have hepatocellular carcinoma (HCC) among patients with complicated hepatitis-C virus (HCV) infection.

Methods: Patients with uncomplicated (U-HCV) or complicated HCV underwent clinical and ultrasonographic (US) evaluations and assessment for the computerized hepatorenal index, hepatic steatosis index and fibrosis indices. Blood samples were obtained for estimation of serum levels of alpha-fetoprotein (AFP) and tumor necrosis factor-α (TNF-α), and plasma expression levels of miR-21 and miR-126 using the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR).

Results: Serum levels of AFP and TNF-α were significantly higher in samples of HCV-HCC patients than controls and other HCV patients. Plasma levels of miR-21 were the highest, while miR-126 levels were the lowest in samples of HCV-HCC patients with significant differences in comparison to samples of controls and other HCV patients. The ROC curve analysis defined high plasma miR-21 levels as specific predictor for HCV infection, and could identify samples of complicated HCV, and samples of HCV-HCC patients, while estimated plasma levels of miR-126 could be applied to screen for HCV and its related complications.

Conclusion: Deregulated plasma expression levels of miR-21 and miR-126 might distinguish cases of HCV complicated by HCC and define cases of HCV-LC, even those that showed low Fib-4 scores.

Keywords:
Hepatitis-C vírus; hepatocellular carcinoma; liver cirrhosis; hepatosteatosis; MicroRNAs; tumor necrosis factor-α; alpha-fetoprotein

•Distinguishing complicated from non-complicated HCV is still a matter of debate.

•Differentiation of complicated cases depending on clinical scores may be misleading.

•Deregulated plasma expression levels of microRNA help in diagnosis of multiple diseases.

•Deregulated expression levels of microRNA 21 and 126 might be helpful for defining cases with complicated HCV.

Name	Sequence (5’-3’)
miR-126F	ACACTCCAGCTGGGCATTATTACTTTTGGT
miR-126R	TGTCGTGGAGTCGGCAATTC
miR-21F	TGAGACTGATGTTGACTGTTGAA’
miR-21R	TGTCAGACAGCCCATCGAC
GAPDH F	CCACCCATGGCAAATTCCATGGCA
GAPDH R	TCTAGACGGCAGGTCAGGTCCAC

			U-HCV	Complicated HCV
				HCV-HS	HCV-LC	HCV-HCC
Number (%)			27 (22.5%)	31 (25.8%)	39 (32.5%)	23 (19.2%)
Age (years)			38 (5.8)	48 (9.6)*	54 (6)*†	55.5 (6.8)*†
Gender	Males		16 (59.3%)	13 (41.9%)	22 (56.4%)	13 (56.5%)
	Females		11 (40.7%)	18 (58.1%)	17 (43.6%)	10 (43.5%)
Body mass index (kg/m²)	Average		0	0	3 (7.7%)	2 (8.7%)
	Overweight		10 (37%)	5 (16.1%)	21 (53.8%)	12 (52.2%)
	Obese grade-I		17 (63%)	22 (71%)	13 (33.3%)	7 (30.4%)
	Obese grade-II		0	4 (12.9%)	2 (5.2%)	2 (8.7%)
	Mean (SD)		29.87 (1.8)†	32.12 (2.3)	29.2 (3)†	29.7 (3.3)†
Lab data	FBG (mg/dl)	Mean (SD)	115 (12)	130 (15.7)*	138 (19.5)*	120 (16.9)‡
		DM	5 (18.5%)	11 (35.5%)	12 (30.8%)	6 (26.1%)
	Hemoglobin conc. (g %)		12.85 (1.7)	13 (2.1	13 (1.4)	12.7 (1.6)
	Total leucocyte count (10³/cc)		6.3 (1.5)	7 (1.6)	6.1 (1.7)	7.3 (1.7)
	Platelet count (10³/cc)		176 (48.5)	192 (39.4)	179 (23.5)	173 (19.7)
	Total bilirubin (mg/ml)		1.22 (0.31)	1.13 (0.23)	1.25 (0.24)	1.2 (0.12)
	Serum albumin (g/ml)		3.9 (0.44)	4.2 (0.23)	4.1 (0.46)	4.3 (0.37)
	Serum AST (U/L)		65 (36.1)	60 (17.1)	74 (12.4)	68 (10.4)
	Serum ALT (U/L)		78 (33.4)	65 (35.7)	59 (32.2)	67 (29.6)
	AST/ALT ratio		0.82 (0.36)	1.09 (0.47)	1.41 (0.37)*†	1.19 (0.47)*

Group Test		U-HCV	Complicated HCV
			HCV-HS	HCV-LC	HCV-HCC
Mean (SD) of US detected hepatosteatosis index		36 (1.52)	38.3 (2.24)*	42.4 (3.36)*†	43 (2.97)*†
Mean (SD) of US detected fibrosis indices	APRI index	1.144 (0.77)	0.347 (0.1)*	1.62 (0.36)*†	1.284 (0.34)†‡
	Fibrosis-4 scores	1.68 (0.77)	1.12 (0.43)	5.1 (0.98)*†	4.39 (1.07)*†‡
Fibrosis grade	No	18 (66.7%)	17 (54.8%)	0	0
	Moderate	9 (33.3%)	14 (45.2%)	6 (15.4%)	4 (17.4%)
	Severe	0	0	33 (84.6%)	19 (82.6%)
Hepatorenal index	<5%	12 (44.4%)	5 (16.1%)	7 (17.9%)	3 (13%)
	>5-25%	8 (29.6%)	15 (48.4%)	15 (38.5%)	5 (21.7%)
	>25-60	5 (18.5%)	8 (25.8%)	13 (33.3%)	15 (65.3%)
	>60	2 (7.5%)	3 (9.7%)	4 (10.3%)	0

Group Biomarker	Control	U-HCV	Complicated HCV
			HCV-HS	HCV-LC	HCV-HCC
AFP (ng/mL)	19 (4.2)	119 (24.8)*	125 (18.3)*	237 (68.4)*†‡	471 (215.8)*†‡ˆ
TNF-α (ng/mL)	13 (3.2)	27 (6.5)*	46 (9)*†	52 (10.6)*†	61 (14.8)*†‡ˆ
miR-21 (FC)	4765 (1127)	6427 (904)*	6896 (955)*	7409 (843)*†	9380 (835)*†‡ˆ
miR-126 (FC)	4492 (984)	3920 (996)	4235 (1129)	3409 (718)*‡	3017 (811)*†‡

Differentiation between samples of	Analysis	Receiver operating characteristic (ROC) curve				Paired-sample analysis of AUCs-difference under the ROC curves
	Variates	AUC	Std. E	P	95% CI	AUC diff	P	95%CI
HCV patients and controls	TNF-α	0.954	0.022	<0.001	0.911-0.997	0.043	0.048	0-0.087
	miR-21	0.998	0.002	<0.001	0.993-1.00
	miR-126	0.271	0.062	0.003	0.149-0.393
Complicated HCV and U-HCV patients	TNF-α	0.790	0.047	<0.001	0.698-0.882	0.144	0.007	0.039-0.248
	miR-21	0.934	0.022	<0.001	0.891-0.977
	miR-126	0.386	0.063	0.027	0.263-0.506
HCC-HCV and both HCV-HS and HCV-LC patients	TNF-α	0.832	0.052	<0.001	0.730-0.934	0.127	0.025	0.016-0.238
	miR-21	0.959	0.021	<0.001	0.918-1.00
	miR-126	0.275	0.059	0.001	0.159-0.391
HCV-HS and HCV-LC patients	TNF-α	0.371	0.066	0.064	0.240-0.501	0.298	0.002	0.105-0.490
	miR-21	0.668	0.068	0.016	0.535-0.801
	miR-126	0.259	0.063	0.001	0.136-0.382

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[TFN1] FBG: fasting blood glucose; AST: aspartate transaminase; ALT: alanine transaminase; *significant difference versus U-HCV; †significant difference versus HCV-HS; ‡significant difference versus HCV-LC, significance was at P<0.05.