HCC is the sixth most common cancer worldwide; also it is the third most common cause of mortality and poor-survival due to the recurrence of HCC and metastasis .
The incidence of liver cancer is one of the highest cancers in Egypt, also it is the fifth most common cancer in both genders and the prognosis for patients with HCC is generally poor . So, early diagnosis of HCC is mandatory for the development of specific curative therapies.
MiRNAs are small, non-coding RNAs which involved in many biological functions, they are critical post-transcriptional regulators in gene expression, modulating cell metabolism, and cell survival . MiRNAs variation may affect its structure and expression. Also, deregulated miRNA and its associated post-transcriptional gene silencing or gene expression suggested being an important part of the pathogenesis of HCC .
MiR196 family consists of miR-196-a1, miR196-a2, and miR-196b. Two mature miRNAs, miR-196a-5p, and miR-196a-3p are generated from hsa-mir-196a-2 with the studied polymorphism, rs11614913, residing in the 3′ arm. Thus, the potential targets of miR-196a could be influenced by its altered expression patterns .
The role of miR-196 in different cancer types is mostly unknown. Although many studies not only suggest the oncogenic function of miR-196, but also it is suggested that miR-196 may play a tumor-suppressive action. If the miR-196 has a dominant action on the inhibition of oncogenic molecules, it will play a tumor suppressor function. However, if the miR-196 mainly targets tumor suppressors, it will play an oncogenic effect .
Many studies suggest that miR-196a could play an important role in pathogenesis and malignant behavior of HCC by targeting many genes, such as HOX gene, HMGA2, and annexin A1 . HOX proteins disorders were suggested to play an important role in malignant transformation and metastasis of HCC. ANXA1 involved in many biological processes by acting as a mediator of apoptosis and inhibitor of cell differentiation. So, ANXA1 may participate in the pathogenesis of HCC .
SNPs in the miR-196a2 (rs11614913) affect the development of cancer susceptibility due to their targeting on several vital genes . Therefore, the present study was designed to evaluate the role of miR-196a2 rs11614913 polymorphism in the development of HCC in the Egyptian population.
The present study shows that the HCV-positive patients accounted for 73 (91.2%) and HBs Ag about 2 (2.5%) of HCC patient group. Dessouky et al. reported that more than 75% were positive for HCV-antibody among Egyptian patients with HCC .
Considering miR-196a2 rs11614913 polymorphism, the results of the present study show that, genotype distribution among the studied groups showed a statistically significant difference between HCC patients and each of the other groups. HCC patients had a higher incidence of CC and TC genotypes when compared to cirrhotic patients and healthy controls (P = 0.02, 0.005), respectively. Allele frequencies showed a statistically higher incidence of C allele in HCC patients compared to cirrhotic patients and healthy controls (P = 0.003).
These results are similar to the results obtained by Li et al. and Yan et al. who found that there was a significant difference in the distribution of miR-196a2 genotypes and alleles between HCC cases and the two other groups [17, 18].
In contrast with the present study, Chu et al. stated that the miR-196a2 genotype distribution among HCC patients was not significantly different from that among the two other groups .
Also in a meta-analysis done by Liu et al. , it has been found that the miR-196a2 genotypes were associated with a decreased susceptibility of HCC frequency.
On the other hand, Tian and his colleagues reported that the distribution of the miR-196a2 (rs11614913) polymorphism did not affect HCC susceptibility .
In the present study, the comparison of the polymorphism between the control and the HCC groups confirmed that both TC genotype and CC genotype were associated with a significantly increased risk of HCC when compared with the TT genotype.
Moreover, when comparing (C) allele versus (T) allele distributions in the studied groups, C allele was found to be associated with a significantly increased risk of HCC with 2.30-fold (OR = 2.30, 95% CI = 1.40–3.76).
Our results are comparable to the results obtained by Zhao et al. , who found that both CC genotype and C allele is at increased risk for HCC “CC vs TT (OR = 1.302, 95% CI = 1.019–1.663) and C vs. T (OR = 1.130, 95% CI = 1.004–1.272)”.
Also, Yan et al.  reported that individuals carrying the TC and CC genotypes of miR-196a2 were found to be associated with an elevated risk of HCC compared to the TT genotype, with an adjusted odds ratio of 1.50 (1.03–2.17) and 2.86(1.60–5.16), respectively.
In contrast to the present study, Chu et al.  suggested that the interaction between studied gene polymorphisms and cancer risk factors was not statistically significant.
The present study shows that the TC + CC genotypes were significantly associated with 3.24-fold increased risk of HCC when compared with the TT genotype (OR = 3.24, 95% CI = 1.55–6.78).
Li et al. documented that the TC + CC genotypes of rs11614913 polymorphism were significantly associated with an increased risk of HCC (TT vs. CT + CC: OR = 2.52, 95% CI = 1.18–4.19; P < 0.05) .
Also, Chen et al.  stated that the rs11614913 polymorphism of miR-196a-2 carry a significant increased risk for HCC development (C vs T: OR = 1.14, 95% CI = 1.06–1.23, P = 0.001; CC vs TT: OR = 1.31, 95% CI = 1.12–1.53, P = 0.001; TC + CC vs TT: OR = 1.16, 95% CI = 1.03–1.31, P = 0.018; CC vs TT: OR = 1.14, 95% CI = 1.00–1.30, P = 0.043).
In the contrary, a meta-analysis done by Peng et al.  stated that there was no evidence of significant association between miR-196a2 rs11614913 polymorphism and HCC risk when all eligible studies were pooled into the meta-analysis (CC vs TT: OR = 1.287, 95% CI = 0.931–1.607, P = 0.226; TC vs TT: OR = 1.055, 95% CI = 0.958–1.161, P = 0.278; TC + CC vs TT: OR = 1.134, 95% CI = 0.974–1.320, P = 0.105.
Additionally, the results obtained by Kim and his colleagues reported that the miR-196a-2 rs12304647 CC genotype had a protective effect against the development of HCC in patients with chronic hepatitis B infection and cirrhosis .
In the present study, there is no statistically significant difference between HCC and cirrhotic groups as regarding genotypes and alleles P = 0.13, 0.09, respectively.
Study of the correlation between miR-196a2 genotypes and personal history and clinical data, including spleen, liver, ascites, child classification, encephalopathy, and tumor size, shows that there was no statistically significant difference data among HCC patients as regards personal history and clinical data.
Chu et al.  suggested that a significant association between miRNA499 SNPs and HCC is present. However, gene-environmental interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter the HCC susceptibility.
Studying the correlation between miR-196a2 rs11614913 genotypes and laboratory characteristics, there was no statistically significant difference between the different genotypes among the HCC cases regarding lab investigations (ALT, AST, albumin, total and direct bilirubin, INR, and AFP).
In our analysis of the association between this polymorphism and the HCC aggressiveness as regards the AFP level and size and number of the focal lesions, we noticed that there was no statistically significant difference between the different genotypes regarding either the level of AFP (P value, 0.76) or the size and number of the focal lesions (P value, 0.99). However, 66.7% of patients with the CC genotype had a high level of AFP. Moreover, 61.9% of patients with the CC genotype had multiple focal lesions.
Li and his co-workers reported that, in a subsequent analysis of the association between microRNA-196a2 and clinic-pathological characteristics, there was an association between rs11614913 genotype and tumor size (P = 0.046), but not with tumor number .