**4. Prognostic potential of microRNA for hepatocarcinoma**

In the past decades, growing evidence has exhibited that microRNAs can act as prognostic biomarkers for hepatocarcinoma [56, 77–101], and **Table 3** summarizes these significantly affecting hepatocarcinoma outcomes. Functionally, the microRNAs affect hepatocarcinoma prognosis The Diagnostic and Prognostic Potential of MicroRNAs for Hepatocellular Carcinoma http://dx.doi.org/10.5772/intechopen.72276 113


Similarly, Jiang et al. [59] and Zhou et al. [64] also attempted to identify possible combination of different microRNAs for increasing diagnostic accuracy of hepatocarcinoma on the basis of different controls with or without liver diseases. They found that the panel consisting of miR-10b, miR-106b, and miR-181a as well as the combination of miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a, and miR-801 can improve detection of hepatocarcinoma. These reports indicate that the panel of microRNAs may have better performance than a single-microRNA assay.

AFP has been regarded as the most important marker for hepatocarcinoma screening and diagnosis, ever since it was identified in the peripheral blood samples from patients with hepatocarcinoma in 1964 [8, 71, 72]. However, this marker is relatively unsatisfactory because of its low sensitivity and specificity. This is mainly because only 60–80% of cases with hepatocarcinoma show positive AFP, whereas about 40% of cirrhotic patients also exhibit different degree increasing level of serum AFP [73, 74]. Thus, AFP may not be a reliable hepatocarcinoma marker, especially for early-stage and/or AFP-negative hepatocarcinoma. On the basis of low sensitivity and specificity of AFP for hepatocarcinoma diagnosis, the American Association for the Study of Liver Disease Practice Guidelines has thrown it away for prognostic surveillance and tumor diagnosis [75]. However, recent studies have displayed that the combination of AFP in the peripheral blood and microRNAs in body fluids may improve the sensitivity and specificity of hepatocarcinoma diagnosis and increase their diagnostic poten-

For example, Wu et al. [55] investigated the joint diagnostic value of serum microRNA-4651 and AFP for hepatocarcinoma in 279 hepatocarcinoma patients, 324 controls with liver injury, and 338 healthy controls. Their results imply that serum microRNA-4651 has higher expression level among cases with hepatocarcinoma (AUC of 0.85; sensitivity of 78.1% and specificity of 92.1%); this increasing expression also displays higher diagnostic potential than AFP at cutoff of 20 ng/mL (AFP20) (AUC = 0.80, sensitivity = 61.3%, and specificity = 98.8%) and of 400 ng/mL (AFP400) (AUC = 0.72, sensitivity = 43.0%, and specificity = 100.0%). Noticeably, the combination of serum microRNA-4651 with AFP significantly improves the discrimination power between patients with hepatocarcinoma and with chronic nontumor liver injury (AUC = 0.90, sensitivity = 83.2%, and specificity = 97.1%). Similar findings have also been observed in the analyses of combination of serum AFP and other microRNAs, such as miR-29a, miR-29c, miR-133a, miR-143, miR-145, miR-192, miR-505, miR-16, miR-195, and miR-199a [14, 47, 58, 65–67, 69, 70, 76]. Altogether, these data suggest that the combination of microRNAs with AFP may improve diagnostic potential of hepatocarcinoma.

**4. Prognostic potential of microRNA for hepatocarcinoma**

In the past decades, growing evidence has exhibited that microRNAs can act as prognostic biomarkers for hepatocarcinoma [56, 77–101], and **Table 3** summarizes these significantly affecting hepatocarcinoma outcomes. Functionally, the microRNAs affect hepatocarcinoma prognosis

**3.3. Diagnostic potential of microRNAs binding with AFP for hepatocarcinoma**

tial [14, 47, 55, 58, 65–67, 69, 70, 76].

112 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment


via the following pathways: (1) promoting cancerous growth and proliferation [77, 78, 80, 83, 89, 98, 99, 102–113], (2) inhibiting cancerous apoptosis [77, 78, 86, 99, 101, 107–109, 111, 112, 114], (3) increasing microvessel density in the tumor tissues [77, 115], (4) affecting cell cycles [24, 25, 27, 28, 116–119], (5) increasing the risk of tumor metastasis [77, 115], and (6) decreasing the sensitivity of cancer cells to anticancer drugs [115]. For example, Lu et al. [115] investigated the prognostic potential of microRNA-1268a for hepatocarcinoma in 411 patients with hepatocarcinoma. Their results imply that microRNA-1268a expression in the cancerous tissues is significantly related to tumor features including tumor volume, stage and grade, and microvessel density. Results from multivariable factors analyses based on Cox regression models show that microRNA-1268a expression is independent of other known prognostic factors for hepatocarcinoma. Furthermore, transarterial chemoembolization (TACE) treatment can improve the prognosis of hepatocarcinoma patients with low microRNA-1268a expression, but not for those with high microRNA-1268e expression. These data imply that the dysregulation of microRNA-1268a can modify the response of cancer cells to antidrugs. Their following studies prove that upregulated microRNA-1268a inhibited while its downregulation enhanced doxorubicin

**MicroRNAs Source Expression level Prognostic significance HR** 

Downregulated Decreasing expression correlates with poor RFS

The Diagnostic and Prognostic Potential of MicroRNAs for Hepatocellular Carcinoma

Downregulated Decreasing expression correlates with poor RFS

Upregulated Increasing expression correlates with poor OS

Downregulated Decreasing expression correlates with poor OS

/ Increasing expression correlates with good OS

Downregulated Decreasing expression correlates with poor OS

Upregulated Increasing expression correlates

Downregulated Increasing expression correlates

Downregulated Decreasing expression correlates with poor OS

Abbreviation: miR, microRNA; OS, overall survival; RFS, tumor recurrence-free survival; HR, hazard ratio; CI,

with poor OS and RFS

with good OS and RFS

miR-30a Tumor

miR-99a Tumor

miR-106b Tumor

miR-130a Tumor

miR-19b Tumor

miR-148a Tumor

miR-372 Tumor

miR-630 Tumor

miR-100 Tumor

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

**Table 3.** The microRNAs as prognostic biomarkers for hepatocarcinoma.

confidence interval; Refs, references.

**(95%CI)**

http://dx.doi.org/10.5772/intechopen.72276

RFS, 3.2 (1.5–6.8)

RFS, 1.60 (1.00–2.50)

OS, 2.00 (1.13–6.98)

OS, 2.22 (1.10–4.46)

OS, 0.45 (0.24–0.85)

RFS, 6.83 OS, 9.53

OS, 0.71 (0.26–1.92) RFS, 0.66 (0.33–1.35)

OS, 1.66 (1.32–2.82)

/ [98]

**Refs**

115

[94]

[79]

[95]

[96]

[97]

[99]

[100]

[101]


Abbreviation: miR, microRNA; OS, overall survival; RFS, tumor recurrence-free survival; HR, hazard ratio; CI, confidence interval; Refs, references.

**Table 3.** The microRNAs as prognostic biomarkers for hepatocarcinoma.

**MicroRNAs Source Expression level Prognostic significance HR** 

miR-500 Serum Upregulated Decreasing expression correlates

Upregulated Increasing expression correlates with poor RFS

Downregulated Decreasing expression correlates with poor RFS

Downregulated Decreasing expression correlates with poor RFS

/ Decreasing expression correlates with poor RFS

Downregulated Decreasing expression correlates with poor OS

Downregulated Decreasing expression correlates

Downregulated Decreasing expression correlates

Upregulated Increasing expression correlates with poor OS

Upregulated Increasing expression correlates

Downregulated Decreasing expression correlates

Downregulated Decreasing expression correlates with poor OS

Downregulated Decreasing expression correlates

Downregulated Decreasing expression correlates with poor OS

Upregulated Increasing expression correlates

Upregulated Increasing expression correlates

Upregulated Increasing expression correlates

Upregulated Increasing expression correlates with poor OS

with tumor resected

with poor OS and RFS

with poor OS and RFS

with poor OS and RFS

with poor OS and RFS

with poor OS and RFS

with poor OS and RFS

with poor OS and RFS

with poor and RFS

miR-96 Tumor

miR-92a Tumor

miR-22 Tumor

miR-375 Tumor

miR-148b Tumor

miR-101 Tumor

miR-19a Tumor

miR-210 Tumor

miR-224 Tumor

miR-29 Tumor

miR-139-5p Tumor

miR-1 Tumor

miR-199b-5p Tumor

miR-130b Tumor

miR-9 Tumor

miR-25 Tumor

let-7 Tumor

tissues

114 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

tissues

**(95%CI)**

RFS, 1.60 (1.00–2.50)

/ [126]

/ [80]

/ [127]

RFS, 3.273 [81]

/ [84]

/ [80]

/ [85]

/ [86]

/ [87]

OS, 2.79 [88]

/ [89]

/ [91]

/ [93]

[90]

[92]

RFS, 4.00 (1.58–7.90) OS, 2.52 (1.02–7.90)

RFS, 1.62 OS, 2.18

OS, 1.86 (1.23–2.98)

RFS, 2.56 (1.32–5.69) OS, 3.27 (1.18–6.92) **Refs**

[79]

[82]

[83]

via the following pathways: (1) promoting cancerous growth and proliferation [77, 78, 80, 83, 89, 98, 99, 102–113], (2) inhibiting cancerous apoptosis [77, 78, 86, 99, 101, 107–109, 111, 112, 114], (3) increasing microvessel density in the tumor tissues [77, 115], (4) affecting cell cycles [24, 25, 27, 28, 116–119], (5) increasing the risk of tumor metastasis [77, 115], and (6) decreasing the sensitivity of cancer cells to anticancer drugs [115]. For example, Lu et al. [115] investigated the prognostic potential of microRNA-1268a for hepatocarcinoma in 411 patients with hepatocarcinoma. Their results imply that microRNA-1268a expression in the cancerous tissues is significantly related to tumor features including tumor volume, stage and grade, and microvessel density. Results from multivariable factors analyses based on Cox regression models show that microRNA-1268a expression is independent of other known prognostic factors for hepatocarcinoma. Furthermore, transarterial chemoembolization (TACE) treatment can improve the prognosis of hepatocarcinoma patients with low microRNA-1268a expression, but not for those with high microRNA-1268e expression. These data imply that the dysregulation of microRNA-1268a can modify the response of cancer cells to antidrugs. Their following studies prove that upregulated microRNA-1268a inhibited while its downregulation enhanced doxorubicin (an anticancer drug)-induced the death of tumor cells. Similarly, Liu et al. [77] and Huang et al. [78] investigated the roles of microRNAs, such as microRNA-24 and microRNA-429, in the tumorigenesis of liver cancer on the basis of analyses of hepatocarcinoma samples and genic toxicity induced by aflatoxin B1 and found the dysregulation of these microRNAs increased microvessel density and mutation frequency of TP53 gene possibly resulting from the loss of DNA repair capacity. Taken together, these reports indicate that microRNAs in body fluids and cancerous tissues may be important candidate biomarkers for hepatocarcinoma prognosis.

However, there are several issues to be noted. First, research on the diagnostic and prognostic potential of microRNAs is still in the early stages, and challenges are noticeable in the clinical utilization of significant microRNAs. Second, in spite of these biomarkers that are discussed well, their therapeutic potential still remains unclear. Finally, although the diagnostic and prognostic potential of microRNAs is well evaluated on the basis of retrospective case-control studies, results from the prospective, randomized controlled trials are absent. Finally, because of the polygenic feature for hepatocarcinoma development, it is essential for a panel of biomarkers to determine high-risk individuals. Thus, the advances in the fields of microRNAs including their origins, stability, detection strategies, variant characteristics, and biofunctions in hepatocarcinoma will progress microRNAs in body fluids to become possible tools for

The Diagnostic and Prognostic Potential of MicroRNAs for Hepatocellular Carcinoma

http://dx.doi.org/10.5772/intechopen.72276

117

The authors declare no competing financial interests. This study was supported in part by the National Natural Science Foundation of China (nos. 81760502, 81572353, 81372639, 81472243, 81660495, and 81460423), the Innovation Program of Guangxi Municipal Education Department (nos. 201204LX674 and 201204LX324), Innovation Program of Guangxi Health Department (no. Z2013781), the Natural Science Foundation of Guangxi (nos. 2017GXNSFGA198002, 2017GXNSFAA198002, 2016GXNSFDA20380003, 2015GXNSFAA139223, 2013GXNSFAA019251, 2014GXNSFDA20118021, and 2014GXNSFAA118144), the Youth Natural Science Foundation of Guangxi Medical University (no. GXMUYSF201522), Research Program of Guangxi "Zhouyue Scholar" (no. 2017–38), Research Program of Guangxi Specially Invited Expert (no. 2017-6th), Research Program of Guangxi Clinic Research Center of Hepatobiliary Diseases (no. AD17129025), and Open Research Program from Molecular Immunity Study Room Involving in Acute & Severe Diseases in Guangxi Colleges and Universities (nos. kfkt20160062 and kfkt20160063).

hepatocarcinoma diagnosis and prognosis in the future.

**Conflicts of interest and source of funding**

AUC the area under the receiver operating characteristic curve

**Abbreviations**

AFP α-fetoprotein

AFB1 aflatoxin B1

CT computed tomography

HCC hepatocellular carcinoma

MRI magnetic resonance imaging

HBV hepatitis virus B

HCV hepatitis virus C
