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

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