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Introduction
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third most common cause of cancer-related death worldwide (1,2). Development of HCC is considered as a discriminative event because it occurs in chronically damaged tissue due to chronic hepatitis and liver cirrhosis, whereas other common malignancies develop on otherwise healthy tissue (3–5). Because of the accumulated genome instability and numerous epigenetic alterations induced by the microenvironment of the background liver, HCC is a more heterogeneous disease (3).
Aberrant DNA methylation is one of the most common epigenetic alterations in malignancies and is specific to individual organs and diseases (6–8). Furthermore, several studies have shown that aberrant DNA methylation contributes to the initiation and progression of malignant tumors through inactivation of tumor suppressors (9,10). Therefore, identification of novel methylated genes is important for the development of both diagnostic markers and therapeutic targets, such as demethylation agents.
Kallmann syndrome-1 gene (KAL1), also named anosmin-1, encodes an extracellular matrix (ECM) related protein with a role in cellular adhesion. KAL1 contains a WAP domain and three FnIII domains, and promotes the migration of gonadotropin-releasing hormone neurons from the olfactory placode to the hypothalamus during development (11–13). KAL1 also induces neurite outgrowth and cell migration through fibroblast growth factor receptor 1 (FGFR1) pathways (14,15). Studies have demonstrated that ECM proteins play a vital role in proliferation and invasion of tumor cells (16). However, to date, conflicting results have been reported regarding the oncological role of KAL1. Decreased KAL1 expression is observed in colon, lung, and ovarian cancers compared with corresponding adjacent normal tissues (17). Conversely, KAL1 overexpression promotes brain tumor malignancy through integrin signal pathways and facilitates colon cancer cell migration and anti-apoptotic capacity (15). These studies indicate that KAL1 exhibits diverse functions in cancer initiation and progression. To the best of our knowledge, there have been no studies of expression analysis of KAL1 in HCC. Moreover, although loss-of-function mutations of the KAL1 gene have been known to underlie Kallmann syndrome (18,19), the significance of the methylation status of the KAL1 gene has yet to be determined.
In our previous microarray project exploring HCC-related tumor suppressors, we found that KAL1 was downregulated in HCC tissues (Log2 ratio: −2.1) (16,20–22). Accordingly, we hypothesized that KAL1 might...