Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma

doi:10.3748/wjg.v29.i31.4706

Advanced Search

BPG is committed to discovery and dissemination of knowledge

Home / Archive / Volume 29, Issue 31

This Article

Academic Content and Language Evaluation of This Article

CrossCheck and Google Search of This Article

Academic Rules and Norms of This Article

Supplementary Materials of This Article

Citation of this article

Corresponding Author of This Article

Research Domain of This Article

Article-Type of This Article

Open-Access Policy of This Article

Times Cited Counts in Google of This Article

Number of Hits and Downloads for This Article

Total Article Views (4931)

All Articles published online

The chart showing PDF series, WORD series, HTML series, Figures (1-3) series, Tables (1-11) series.

Item

Count

PDF

120

WORD

HTML

2556

Figures (1-3)

287

Tables (1-11)

466

Sum=3455

Featured Article

The chart showing Browse series, Download series.

Item

Count

Browse

143

Download

507

Sum=650

Publishing Process of This Article

Item

Count

Browse

173

Download

459

Sum=632

Aug 21, 2023 (publication date) through Nov 23, 2024

Times Cited of This Article

Times Cited (6)

Journal Information of This Article

Publication Name

World Journal of Gastroenterology

ISSN

1007-9327

Publisher of This Article

Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Review

World J Gastroenterol. Aug 21, 2023; 29(31): 4706-4735
Published online Aug 21, 2023. doi: 10.3748/wjg.v29.i31.4706

Table 1 Efficacy of single microRNAs used in diagnosing hepatitis B virus-associated hepatocellular carcinoma patients from healthy control

miRNA	AUC	Sensitivity	Specificity	Ref.
miR-18a	0.881	0.861	0.750	[228]
miR-26a	0.711	0.876	0.600	[30]
miR-26a¹	0.685	0.907	0.600	[30]
miR-26a-5p	0.762	0.689	0.744	[38]
miR-27a	0.859	0.933	0.733	[30]
miR-27a¹	0.809	0.926	0.733	[30]
miR-34a	0.736	0.920	0.600	[21]
miR-93-5p	0.906	0.859	0.954	[15]
miR-93-5p	0.903	0.879	0.938	[15]
miR-93-5p	0.905	0.862	0.954	[15]
miR-101	0.788	0.761	0.700	[24]
miR-122	0.984	0.960	0.940	[16]
miR-122	0.869	0.816	0.833	[10]
miR-122-5p	0.697	0.489	0.822	[38]
miR-125b	0.835	0.798	0.867	[30]
miR-125b	0.891	0.859	0.786	[23]
miR-125b	0.940	0.830	0.960	[17]
miR-125b¹	0.822	0.815	0.867	[30]
miR-141-3p	0.758	0.681	0.833	[38]
miR-143	0.813	0.776	0.860	[229]
miR-145	0.852	0.882	0.780	[229]
miR-150	0.931	0.825	0.837	[13]
miR-192-5p	0.695	0.719	0.756	[38]
miR-199a-5p	0.638	0.593	0.667	[38]
miR-205	0.885	0.969	0.679	[36]
miR-206	0.615	0.481	0.788	[38]
miR-212	0.886	0.696	0.950	[230]
miR-214	0.747	0.760	0.740	[21]
miR-223	0.736	0.921	0.633	[30]
miR-223¹	0.822	0.907	0.633	[30]
miR-433-5p	0.736	0.793	0.644	[38]
miR-487b	0.946	0.888	0.909	[18]
miR-487b	0.929	0.839	0.928	[19]
miR-768-3p	0.908	0.873	0.800	[20]
miR-1228-5p	0.552	0.793	0.278	[38]
miR-5193	0.993	0.960	1.000	[21]
miR-6510	0.839	0.720	0.910	[21]

¹Comparing early-stage hepatitis B virus-associated hepatocellular carcinoma patients to patients with other stages.

AUC: Area under the receiver operating characteristic curve; miRNAs: MicroRNAs.

Table 2 Efficacy of single microRNAs used in diagnosing hepatitis B virus-associated hepatocellular carcinoma patients from hepatitis B virus-positive patients

Comparison	miRNA	AUC	Sensitivity	Specificity	Ref.
HBV-carriers	miR-20a-5p	0.770	0.866	0.573	[231]
HBV-carriers	miR-25-3p	0.718	0.553	0.793	[231]
HBV-carriers	miR-30a-5p	0.681	0.642	0.683	[231]
HBV-carriers	miR-92a-3p	0.765	0.761	0.683	[231]
HBV-carriers	miR-132-3p	0.722	0.910	0.366	[231]
HBV-carriers	miR-185-5p	0.788	0.910	0.390	[231]
HBV-carriers	miR-320a	0.678	0.388	0.878	[231]
HBV-carriers	miR-324-3p	0.656	0.746	0.500	[231]
CHB	miR-26a	0.650	0.533	0.833	[30]
CHB	miR-26a¹	0.411	0.582	0.500	[30]
CHB	miR-27a	0.761	0.677	0.833	[30]
CHB	miR-27a¹	0.690	0.527	0.833	[30]
CHB	miR-34a	0.619	0.400	0.870	[21]
CHB	miR-96	0.803	0.779	0.753	[34]
CHB	miR-99a²	0.694	0.844	0.567	[232]
CHB	miR-101	0.777	0.881	0.620	[24]
CHB	miR-122	0.190	0.250	0.250	[16]
CHB	miR-122	0.630	0.776	0.578	[10]
CHB	miR-125b	0.675	0.522	0.867	[30]
CHB	miR-125b	0.958	0.938	0.857	[23]
CHB	miR-125b	0.792	0.906	0.567	[232]
CHB	miR-125b	0.800	0.810	0.870	[17]
CHB	miR-125b¹	0.631	0.400	0.870	[30]
CHB	miR-126	0.670	0.630	0.580	[32]
CHB	miR-142-3p	0.550	0.320	0.910	[32]
CHB	miR-150	0.881	0.791	0.765	[13]
CHB	miR-214	0.520	0.850	0.430	[21]
CHB	miR-223	0.737	0.544	0.933	[30]
CHB	miR-223¹	0.656	0.782	0.533	[30]
CHB	miR-224	0.846	0.865	0.745	[11]
CHB	miR-487b	0.815	0.836	0.667	[18]
CHB	miR-487b	0.856	0.759	0.897	[19]
CHB	miR-768-3p	0.819	0.850	0.727	[20]
CHB	miR-5193	0.817	0.798	0.820	[21]
CHB	miR-6510	0.531	0.810	0.390	[21]
HBV-DN	let-7b	0.633	0.825	0.467	[233]
HBV-DN	miR-122	0.648	0.667	0.567	[233]
HBV-LC	miR-26a-5p	0.744	0.607	0.909	[38]
HBV-LC	miR-99a²	0.696	0.967	0.563	[232]
HBV-LC	miR-101	0.976	0.955	0.902	[24]
HBV-LC	miR-122	0.675	0.610	0.760	[37]
HBV-LC	miR-122-5p	0.751	0.489	0.902	[38]
HBV-LC	miR-125b	0.958	0.891	0.881	[23]
HBV-LC	miR-125b	0.910	0.780	0.960	[17]
HBV-LC	miR-126	0.578	0.550	0.580	[32]
HBV-LC	miR-141-3p	0.663	0.607	0.727	[38]
HBV-LC	miR-142-3p	0.566	0.550	0.630	[32]
HBV-LC	miR-192-5p	0.687	0.548	0.833	[38]
HBV-LC	miR-199a-5p	0.589	0.593	0.576	[38]
HBV-LC	miR-205	0.781	0.969	0.542	[36]
HBV-LC	miR-206	0.693	0.778	0.689	[38]
HBV-LC	miR-224	0.832	0.865	0.667	[11]
HBV-LC	miR-433-5p	0.644	0.564	0.674	[38]
HBV-LC	miR-1228-5p	0.542	0.667	0.470	[38]
CHB + HBV-LC	miR-18a	0.775	0.772	0.700	[228]
CHB + HBV-LC	miR-224	0.840	0.865	0.711	[11]
CHB + HBV-LC	miR-375	0.768	0.938	0.639	[234]

¹Comparing early-stage hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) patients to patients with other stages.

²Comparing advanced HBV-HCC to patients with other stages.

CHB: Chronic hepatitis B patient, HBV-DN: Hepatitis B virus-related dysplastic nodule patient; HBV-LC: Hepatitis B virus-related liver cirrhosis patient; AUC: Area under the receiver operating characteristic curve; miRNAs: MicroRNAs.

Table 3 Efficacy of microRNAs panels used in diagnosing hepatitis B virus-associated hepatocellular carcinoma

Comparison	miRNA	AUC	Sensitivity	Specificity	Ref.
HC	miR-125b + miR-223¹	0.881	0.891	0.833	[30]
HC	miR-125b + miR-26a¹	0.884	0.873	0.867	[30]
HC	miR-223 + miR-27a¹	0.892	0.909	0.833	[30]
HC	miR-223 + miR-26a¹	0.828	0.927	0.667	[30]
HC	miR-27a + miR-26a¹	0.895	0.945	0.833	[30]
HC	miR-125b + miR-223 + miR-27a + miR-26a	0.932	0.865	0.933	[30]
HC	miR-125b + miR-223 + miR-27a + miR-26a¹	0.910	0.852	0.933	[30]
HC	miR-375 + miR-25 + and let-7f	0.997	0.979	0.991	[31]
HC	miR-23b + miR-423 + miR-375 + miR-23a + miR-342-3p	0.999	0.969	0.994	[31]
HC	miR-122 + miR-192 + miR-21 + miR-223 + miR-26a + miR-27a + miR-801	0.941	0.832	0.939	[44]
HC	miR-27b-3p + miR-192-5p	0.823	0.685	0.952	[235]
HC	miR-206 + miR-141-3p + miR-433-5p + miR-1228-5p + miR-199a-5p + miR-122-5p + miR-192-5p + miR-26a-5p	0.893	0.828	0.833	[38]
HBV-carriers	miR-20a-5p + miR-25-3p + miR-30a-5p + miR-92a-3p + miR-132-3p + miR-185-5p + miR-320a + miR-324-3p	0.802	0.866	0.646	[231]
HBV-carriers	miR-20a-5p + miR-320a + miR-324-3p + miR-375	0.768	0.650	0.775	[231]
HBV-carriers	miR-20a-5p + miR-320a + miR-324-3p + miR-375	0.706	0.560	0.838	[231]
CHB	miR-125b + miR-223¹	0.680	0.473	0.867	[30]
CHB	miR-125b + miR-26a¹	0.668	0.509	0.833	[30]
CHB	miR-223 + miR-27a¹	0.714	0.582	0.833	[30]
CHB	miR-223 + miR-26a¹	0.708	0.509	0.900	[30]
CHB	miR-27a + miR-26a¹	0.741	0.873	0.533	[30]
CHB	miR-125b + miR-223 + miR-27a + miR-26a	0.761	0.622	0.867	[30]
CHB	miR-125b + miR-223 + miR-27a + miR-26a¹	0.687	0.818	0.533	[30]
CHB	miR-10a + miR-125b	0.992	0.985	0.985	[31]
CHB	miR-122 + miR-192 + miR-21 + miR-223 + miR-26a + miR-27a + miR-801	0.842	0.791	0.764	[44]
HBV-LC	miR-122 + miR-192 + miR-21 + miR-223 + miR-26a + miR-27a + miR-801	0.884	0.750	0.911	[44]
HBV-LC	miR-27b-3p + miR-192-5p	0.859	0.785	0.793	[235]
HBV-LC	miR-206 + miR-141-3p + miR-433-5p + miR-1228-5p + miR-199a-5p + miR-122-5p + miR-192-5p + miR-26a-5p	0.892	0.816	0.846	[38]

¹Comparing early-stage hepatitis B virus-associated hepatocellular carcinoma patients to patients with other stages.

HC: Healthy control, CHB: Chronic hepatitis B patient; HBV-LC: Hepatitis B virus-related liver cirrhosis patient; AUC: Area under the receiver operating characteristic curve; miRNAs: MicroRNAs.

Table 4 Efficacy of microRNAs combined with other biomarkers used in diagnosing hepatitis B virus-associated hepatocellular carcinoma

Comparison	miRNA	AUC	Sensitivity	Specificity	Ref.
HC	miR-125b + miR-27a + AFP¹	0.937	0.909	0.933	[30]
HC	miR-125b + miR-223 + miR-27a + miR-26a + AFP	0.945	0.910	0.933	[30]
HC	miR-125b + miR-223 + miR-27a + miR-26a + AFP²	0.972	0.944	0.900	[30]
HC	miR-125b + miR-223 + miR-27a + miR-26a + AFP¹	0.936	0.907	0.933	[30]
HC	miR-125b + miR-223 + miR-27a + miR-26a + AFP¹^,²	0.956	0.800	1.000	[30]
HBV-carriers	miR-20a-5p + miR-320a + miR-324-3p + miR-375 + AFP	0.789	0.700	0.775	[231]
HBV-carriers	miR-20a-5p + miR-320a + miR-324-3p + miR-375 + AFP	0.767	0.640	0.838	[231]
CHB	miR-96 + AFP	0.889	0.836	0.824	[34]
CHB	miR-126 + AFP	0.920	0.840	0.920	[32]
CHB	miR-142-3p + AFP	0.910	0.860	0.940	[32]
CHB	miR-224 + AFP	0.867	0.875	0.765	[11]
CHB	miR-125b + miR-27a + AFP¹	0.722	0.600	0.833	[30]
CHB	miR-125b + miR-223 + miR-27a + miR-26a + AFP	0.790	0.689	0.867	[30]
CHB	miR-125b + miR-223 + miR-27a + miR-26a + AFP²	0.833	0.820	0.767	[30]
CHB	miR-125b + miR-223 + miR-27a + miR-26a + AFP¹	0.728	0.582	0.867	[30]
CHB	miR-125b + miR-223 + miR-27a + miR-26a + AFP¹^,²	0.812	0.704	0.833	[30]
CHB	miR-126 + miR-142-3p + AFP	0.930	0.880	0.970	[32]
HBV-DN	let-7b + AFP	0.706	0.508	0.767	[233]
HBV-DN	miR-122 + AFP	0.714	0.792	0.533	[233]
HBV-LC	miR-99a + AFP	0.780	0.719	0.828	[232]
HBV-LC	miR-101 + AFP	0.973	0.966	0.879	[24]
HBV-LC	miR-122 + AFP + PIVKA-II	0.918	0.910	0.880	[37]
HBV-LC	miR-126 + AFP	0.897	0.800	0.790	[32]
HBV-LC	miR-142-3p + AFP	0.899	0.850	1.000	[32]
HBV-LC	miR-205 + AFP	0.893	0.750	0.860	[36]
HBV-LC	miR-224 + AFP	0.844	0.969	0.641	[11]
HBV-LC	miR-126 + miR-142-3p + AFP	0.939	0.850	0.840	[32]
CHB + HBV-LC	miR-224 + AFP	0.857	0.875	0.722	[11]

¹Comparing early-stage hepatitis B virus-associated hepatocellular carcinoma patients to patients with other stages.

²Adjusting for gender and age differences.

HC: Healthy control; CHB: Chronic hepatitis B patient; HBV: Hepatitis B virus; HBV-DN: Hepatitis B virus-related dysplastic nodule patient; HBV-LC: Hepatitis B virus-related liver cirrhosis patient; AFP: Alpha fetoprotein; PIVKA-II: Prothrombin induced by vitamin K deficiency or antagonist- II; AUC: Area under the receiver operating characteristic curve; miRNAs: MicroRNAs.

Table 5 Efficacy of microRNAs used in diagnosing hepatitis B virus-associated hepatocellular carcinoma with low alpha fetoprotein expression

AFP level in HBV-HCC patients	Comparison	miRNA	AUC	Sensitivity	Specificity	Ref.
< 15 ng/mL	HBV-DN	let-7b	0.645	0.848	0.500	[233]
< 15 ng/mL	HBV-DN	miR-122	0.629	0.712	0.577	[233]
< 15 ng/mL	HBV-DN	miR-122 + let-7b	0.646	0.848	0.500	[233]
≤ 20 ng/mL	CHB + HC	miR-26a	0.733	0.868	0.574	[30]
≤ 20 ng/mL	CHB + HC	miR-26a¹	0.701	0.880	0.574	[30]
≤ 20 ng/mL	CHB + HC	miR-27a	0.832	0.838	0.723	[30]
≤ 20 ng/mL	CHB + HC	miR-27a¹	0.771	0.800	0.723	[30]
≤ 20 ng/mL	CHB + HC	miR-125b	0.778	0.760	0.790	[30]
≤ 20 ng/mL	CHB + HC	miR-125b¹	0.775	0.800	0.787	[30]
≤ 20 ng/mL	CHB + HC	miR-223	0.759	0.789	0.702	[30]
≤ 20 ng/mL	CHB + HC	miR-223¹	0.715	0.720	0.723	[30]
< 20 ng/mL	CHB + HC	miR-15b + miR-130b	0.980	0.967	0.915	[9]
≤ 20 ng/mL	CHB + HC	miR-125b + miR-223 + miR-27a + and miR-26a	0.874	0.842	0.851	[30]
≤ 20 ng/mL	CHB + HC	miR-125b + miR-223 + miR-27a + miR-26a¹	0.849	0.800	0.894	[30]
< 200 ng/mL	CHB	miR-125b	0.943	1.000	0.755	[23]
< 250 ng/mL	CHB	miR-126	0.765	0.610	0.690	[32]
< 250 ng/mL	HBV-LC	miR-126	0.643	0.610	0.580	[32]
< 400 ng/mL	HBV-LC	miR-205	0.815	1.000	0.560	[36]
20-400 ng/mL	CHB + HC	miR-15b + miR-130b	0.976	1.000	0.915	[9]
< 400 ng/mL	CHB + HBV-LC + HC	miR-122 + miR-192 + miR-21 + miR-223 + miR-26a + miR-27a + miR-801	0.879	0.777	0.845	[44]

¹Comparing early-stage hepatitis B virus-associated hepatocellular carcinoma patients to patients with other stages.

HBV-DN: Hepatitis B virus-related dysplastic nodule patient; CHB: Chronic hepatitis B patient; HC: Healthy control; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HBV-LC: Hepatitis B virus-related liver cirrhosis patient; AFP: Alpha fetoprotein; AUC: Area under the receiver operating characteristic curve; miRNAs: MicroRNAs.

Table 6 Efficacy of microRNAs used to predict the prognosis of hepatitis B virus-associated hepatocellular carcinoma

Tissues/serum	miRNA panels	Risk/protective factors	Outcome	HR	CI	Ref.
Tissues	miR-9-3^a	Risk	OS	-	-	[62]
Tissues	miR-10b^a	Risk	OS	-	-	[62]
Tissues	miR-21^b	Risk	DFS	3.019	0.219-6.939	[56]
Tissues	miR-29a-5p^b	Risk	TTR	0.5	0.3-0.8	[63]
Tissues	miR-29a-5p^b	Risk	OS	-	-	[63]
Tissues	miR-31^a	Risk	OS	-	-	[62]
Tissues	miR-106b^a	Risk	OS, DFS	-	-	[64]
Tissues	miR-122^a	Protect	OS	-	-	[54]
Tissues	miR-122^b	Protect	OS	-	-	[55]
Tissues	miR-143^b	Protect	OS	-	-	[55]
Tissues	miR-145^a	Protect	DFS	1.12	0.293-2.958	[56]
Tissues	miR-193b^c	Protect	OS	-	-	[57]
Tissues	miR-203a	Protect	OS	0.63	0.41-0.97	[58]
Tissues	miR-216b^c	Protect	OS, DFS	-	-	[59]
Tissues	miR-224^b	Risk	OS	-	-	[55]
Tissues	miR-371a-5p^b	Risk	OS	-	-	[27]
Tissues	miR-375	Protect	DFS	-	-	[60]
Tissues	miR-375^b	Protect	OS	-	-	[55]
Tissues	miR-384^a	Protect	OS	-	-	[61]
Tissues	miR-519c^a	Risk	OS	-	-	[62]
Tissues	miR-522^a	Risk	OS	-	-	[62]
Tissues	miR-522^b	Risk	OS	2.19	1.33-3.6	[65]
Tissues	miR-523^b	Risk	OS	1.5	1-2.44	[65]
Tissues	miR-3188^c	Risk	OS, DFS	-	-	[28]
Tissues	miR-3660^a	Risk	OS	-	-	[62]
Tissues	miR-3682-3p^c	Risk	OS	-	-	[66]
Tissues	miR-4784^a	Risk	OS	-	-	[62]
Tissues	miR-5188^b	Risk	OS	-	-	[67]
Tissues	miR-6883^a	Risk	OS	-	-	[62]
Serum	miR-24-3p^b	Risk	OS	2.141	1.158-3.960	[33]
Serum	miR-24-3p^b	Risk	DFS	2.055	1.114-3.792	[33]
Serum	miR-29a-3p^b	Risk	OS	4.0	1.2-13.9	[69]
Serum	miR-29a-3p^a	Risk	PFS	-	-	[69]
Serum	miR-96^a	Risk	OS	-	-	[34]
Serum	miR-150^c	Protect	OS	0.446	0.233-0.854	[13]
Serum	miR-192-5p^b	Risk	OS	-	-	[69]
Serum	miR-192-5p^b	Risk	PFS	2.2	1.1-4.2	[69]
Serum	miR-487b^a	Risk	OS	2.846	1.139-7.114	[19]
Serum	miR-487b^c	Risk	OS	2.115	1.083-4.132	[18]
Serum	miR-768-3p^b	Protect	OS	3.057	1.136-8.225	[20]
Plasma	miR-155	Risk	OS	-	-	[70]

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

OS: Overall survival; DFS: Disease-free survival; TTR: Time to tumor recurrence; PFS: Progression-free survival; HR: Hazard ratio; CI: Confidence interval; miRNAs: MicroRNAs.

Table 7 Dysregulated signaling pathways mediates hepatitis B virus-induced microRNAs dysregulation

Upstream signaling pathway	miRNA	HBV protein	Expression	Ref.
ERK1/2/CREB	miR-212-3p	HBe	Up	[85]
MAPK/Ap1	miR-21	HBx	Up	[87,88]
MAPK/YY1	miR-129-2	HBV	Down	[89]
MAPK/YY1	miR-203	HBV	Down	[89]
MAPK/YY1	miR-335	HBV	Down	[89]
IL-6/STAT3	miR-21	HBx	Up	[91]
STAT3	miR-328-3p	HBV, HBx, HBc	Up	[90]
STAT3	miR-34a	HBx	Down	[95]
STAT3/SALL4	miR-200c	HBV	Down	[94]
STAT3	miR-204	HBV	Down	[93]
STAT3	miR-539	HBx	Up	[92]
NF-κB	miR-23a	HBV	Up	[103]
NF-κB	miR-143	HBx	Up	[98,99]
NF-κB	miR-146a	HBx	Up	[100]
NF-κB	miR-146a-5p	HBx, HBc	Up	[97]
NF-κB	miR-1269b	HBx	Up	[74]
PI3K, NF-κB	miR-155	HBe	Up	[101]
IKKα/NF-κB	miR-7	HBx	Up	[104]
IKKα/NF-κB	miR-21	HBx	Up	[104]
IKKα/NF-κB	miR-103	HBx	Up	[104]
IKKα/NF-κB	miR-107	HBx	Up	[104]
Androgen pathway	miR-216a	HBx	Up	[111]
TLR7/NF-κB	miR-155	HBV	Down	[106]
LEF-1	miR-371a-5p	HBV	Up	[27]
PPARγ/NF-κB/p65	miR-130a	HBV	Down	[105]

HBV: Hepatitis B virus; HBe: Hepatitis B virus envelope antigen; HBx: Hepatitis B virus x protein, HBc: Hepatitis B virus core antigen; miRNAs: MicroRNAs.

Table 8 Dysregulated transcription factors or upstream regulatory elements mediates hepatitis B virus-induced microRNAs dysregulation

Transcription factors or upstream regulatory elements	miRNA	HBV protein	Expression	Ref.
c-Myc	let-7	HBx	Down	[115]
c-Myc	miR-15a/16	HBx	Down	[114]
c-Myc	miR-17-92	HBV	Up	[116]
c-Myc	miR-192	HBx	Down	[113]
c-Myc	miR-3682-3p	HBx	Up	[66]
CREB1	miR-520c-3p	HBx	Up	[117]
CREB	miR-3188	HBx	Up	[28]
Survivin, Sp1	miR-520b	HBx	Up	[118]
FOXO3	miR-30b-5p	HBp	Up	[119]
URG11	miR-148a	HBx	Up	[126]
JNK/c-Jun	miR-199a-3p	HBx	Up	[120]
p53	miR-216b	HBx	Down	[59]
p53	miR-148a	HBx	Down	[122]
Hnf4α	miR-122	HBV	Down	[123]
Hnf4α	miR-548p	HBx	Down	[124]
DDX3	miR-34	HBx	Down	[127]

HBV: Hepatitis B virus; HBx: Hepatitis B virus x protein; HBp: Hepatitis B virus polymerase protein; miRNAs: MicroRNAs.

Table 9 MicroRNAs sponges dysregulated by hepatitis B virus to induce microRNAs dysregulation

	miRNAs sponges	miRNA	Expression	Ref.
LncRNA	LncRNA Unigene56159	miR-140-5p	Down	[152]
	LncRNA PCNAP1	miR-154	Down	[153]
	LncRNA n335586	miR-924	Down	[154]
	LncRNA H19	miR-138	Down	[131]
	LncRNA H19	miR-22	Down	[155]
	LncRNA TRERNA1	miR-22-3p	Down	[156]
	LncRNA MALAT1	miR-124	Down	[157]
	LncRNA HMMR-AS1	miR-627-3p	Down	[158]
	LncRNA LINC01352	miR-135b	Up	[159]
	LncRNA F11-AS1	miR-211-5p	Up	[160]
	LncRNA XIST	miR-192	Down	[161]
	LncRNA LINC01232	miR-708-5p	Down	[162]
	LncRNA TFAP2A-AS1	miR-933	Up	[163]
	LncRNA LINC00924	miR-6755-5p	Up	[164]
	LncRNA HMGB1	miR-200	Down	[165,166]
CircRNA	CircRNA ARL3	miR-1305	Down	[167]
	CircRNA RNF13	miR-424-5p	Down	[168]
	CircRNA BACH1	miR-200a-3p	Down	[169]
	CircRNA ATP5H	miR-138-5p	Down	[170]
	CircRNA 0027089	miR-136-5p	Down	[171]
HBV mRNAs	HBx mRNA	miR-15a/miR-16-1	Down	[172]
	HBV mRNAs	miR-15a/miR-16	Down	[173]
	HBV mRNAs	miR-122	Down	[174]
	HBV mRNAs	let-7a	Down	[175]
	HBs mRNA	let-7g	Down	[176]
	HBx mRNA	miR-129-5p	Down	[177]
	HBx-LINE1	miR-122	Down	[179]

HBV: Hepatitis B virus; HBx: Hepatitis B virus x protein; HBs: Hepatitis B virus surface protein; miRNAs: MicroRNAs.

Table 10 Functions of hepatitis B virus-dysregulated microRNAs in promoting hepatocellular carcinoma

miRNA	HBV protein	Expression	Target genes	Abnormal function in HBV-HCC	Ref.
miR-7	HBV, HBx	Up	Mapsin	Conferring HBx-mediated anoikis resistance and doxorubicin resistance	[213]
miR-15a/16	HBV mRNA	Down	-	Inducing etoposide-induced apoptosis	[173]
miR-21	HBV, HBx	Up	Mapsin	Conferring HBx-mediated anoikis resistance and doxorubicin resistance	[213]
miR-23a	HBV	Down	CCL22	Inhibiting Tregs recruitment	[103]
miR-30b-5p	HBp	Up	MINPP1	Promoting tumor growth, enhancing cell proliferation, promoting cell migration and invasion, regulating glycolytic bypass metabolism	[119]
miR-34a	HBV	Down	CCL22	Inhibiting Tregs recruitment	[209]
miR-103	HBV, HBx	Up	Mapsin	Conferring HBx-mediated anoikis resistance and doxorubicin resistance	[213]
miR-107	HBV, HBx	Up	Mapsin	Conferring HBx-mediated anoikis resistance and doxorubicin resistance	[213]
miR-124	HBx	Down	PI3K/Akt	Suppressing CSC differentiation	[157]
miR-135a-5p	HBc	Up	VAMP2	Preventing Doxorubicin hydrochloride-induced apoptosis	[212]
miR-138	HBV	Down	PD-1	Regulating cytokine secretion of T cells and improving T-cell immune responses	[208]
miR-146a	HBV	Up	STAT1	Suppressing IFN-induced anti-HBV effect	[187]
miR-152	HBV	Down	HLA-G	Enhanced NK cytolysis against hepatoma cells	[210]
miR-193b	HBV	Down	Mcl-1	Sensitizing sorafenib-induced apoptosis	[57]
miR-200a/200b/429	HBx	Down	RICTOR	Impairing HCC stem cell properties, regulating glutamine metabolism, sensitizing the response to anti-PD-L1 immunotherapy	[165,166]
miR-203a	HBs	Down	BMI1	Sensitizing 5-FU-induced apoptosis, impairing HCC stem cell properties	[58]
miR-205	HBx	Down	ACSL1	May promote lipogenesis	[141] [206]
miR-325-3p	HBV	Down	DPAGT1	Sensitizing the response to Doxorubicin chemotherapy	[201,202]
miR-329	HBV, HBx	Down	AFP	Sensitizing chemotherapy induced apoptosis	[214]
miR-384	HBV, HBx	Down	PTN/PI3K/AKT/mTORC1	Inhibiting high glucose-induced lipogenesis	[61]
miR-429	HBx	Down	Rab18	Inhibiting dysregulation of lipogenesis	[205]
miR-1236	HBV, HBx	Down	AFP	Sensitizing chemotherapy induced apoptosis	[214]
miR-3682-3p	HBx	Up	FOXO3/PI3K/AKT1/β-catenin/c-Myc	Promoting HCC stemness	[66]
miR-5188	HBx	Up	FOXO1/β-catenin	Resisting the effects of chemotherapy 5-FU, CDDP and EPI, promoting HCC stemness	[67]

HBV: Hepatitis B virus; HBx: Hepatitis B virus x protein; HBp: Hepatitis B virus polymerase protein; HBc: Hepatitis B virus core antigen; HBs: Hepatitis B virus surface antigen; HCC: Hepatocellular carcinoma; miRNAs: MicroRNAs.

Table 11 Hepatitis B virus-dysregulated microRNAs that play different roles in hepatitis B virus-associated hepatocellular carcinoma

Process	HBV-dysregulated miRNAs
Tumor stemness	miR-124[157], miR-200a/200b/429[165], miR-203[58], miR-325-3p[201], miR-3682-3p[66], miR-5188[67]
Metabolic reprogramming	miR-30b-5p[119], miR-200[165], miR-205[141,206], miR-384[61], miR-429[205]
Anti-tumor immunity	miR-23a[103], miR-34a[209], miR-138[208], miR-146a[187], miR-152[210], miR-200[165,166]
Drug resistance	miR-7[213], miR-21[213], miR-103[213], miR-107[213], miR-135a-5p[212], miR-5188[67], miR-15a/16[173], miR-193b[57], miR-203a[58], miR-325-3p[201,202], miR-329[214], miR-1236[214]

HBV: Hepatitis B virus; miRNAs: MicroRNAs.

Citation: Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29(31): 4706-4735
URL: https://www.wjgnet.com/1007-9327/full/v29/i31/4706.htm
DOI: https://dx.doi.org/10.3748/wjg.v29.i31.4706