Liver cancer is one of the most lethal cancers in the world, and its mortality ranks the third in cancer deaths [
1,
2]. Each year, about 60 million people worldwide die of liver cancer, and this has a growing trend. Primary liver cancers mainly include two types: hepatocellular carcinoma (HCC) and intrahepatic bile duct cancer [
3]. In the developing countries, hepatitis B and hepatitis C are the risk factors responsible for most cases of primary liver cancer [
4,
5]. Although the risk factors are preventable, the incidence of liver cancer is actually rising in many developing countries. The most common risk factor in the USA is alcohol abuse, followed by obesity and diabetes [
6,
7]. The incidence has gotten over 30,000 cases each year in the USA. Thus, it is very important to elucidate the mechanism for the occurrence and development of hepatocellular carcinoma.
Klotho was a new identified aging suppressor gene, which is highly conserved between human and mouse, with 86 % amino acid identity [
8]. The gene encoded a membrane protein and defect in Klotho gene expression in the mouse that causes a syndrome of aging, including a short lifespan [
9]. Recently, the relationship of Klotho expression and cancer progression has been studied [
10‐
12]; however, the role and mechanism in a variety of cancers remain unclear. Lu et al. had a clinical follow-up study of 189 epithelial ovarian cancer patients, which demonstrated that high expression of secreted Klotho was associated with increased risk of disease progression and death and positively correlated with the expression of IGF-I and IGFBP-3 but not with IGF-II [
11]. However, Wang et al. reported that Klotho, as a novel tumor suppressor gene, was epigenetically inactivated and silenced through promoter hypermethylation in gastric cancer, and the promoter methylation of Klotho could be used to predict the prognosis of gastric cancer patients [
13]. In human colon cancers, expression of Klotho was downregulated and correlated with tumor invasion and Dukes staging, while overexpression of Klotho inhibited cell proliferation and invasion through inhibition of IGF1R-mediated PI3K/AKT pathway in colon cancer cells [
14]. Moreover, Klotho inhibited the capacity of cell migration and invasion in cervical cancer, in vitro restoration of Klotho expression in SiHa cells resulting in a decreased cell motility and invasiveness through upregulation of E-cadherin, downregulation of N-cadherin, and reduced expression of MMP-7 and MMP-9 [
15].
However, the relationship and association between the expression of Klotho and primary liver cancers is not clarified till now [
16]. In the present study, we explored the effects and possible mechanisms relating to Klotho in human liver cancer cell lines, and the clarification of the association and mechanism would contribute to treatment for therapy of liver cancer patients.