**1. Introduction**

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1]. Growing understanding of the multiple pathogenic factors including hepatitis B or C virus (HBV or HCV) infection, toxic, lipid accumulation, aflatoxin B1 intake, and so on with complex molecular mechanisms underlying HCC reveal that hepatocarcinogenesis is a multistep process including lots of activated or suppressed oncogenes or anticancer genes [2–4]. Some techniques for HCC therapy have experienced great progress. However, the prognosis of HCC patients is still very poor due to the high rates of tumor recurrence and metastasis. Effective therapy of HCC is dependent on early specific diagnosis, therefore, to provide optimal treatment for patients, more precise and effective markers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis [5–7]. Numerous studies have shown the clinical utility of novel blood-based markers, such as circulating tumor cells, key signal molecules, long non-coding RNA, and microRNA with great potential for HCC [8, 9].

highly conserved heterodimeric disulfide-linked 449 amino acid polypeptide that represents the major product of CLU gene. The ER-Golgi sCLU is considered to influence immune regulation, transformation, tissue remodeling, lipid transport, membrane recycling, complements cascade, DNA repair, cell adhesion, and cell-cell interactions, indicated that sCLU is widely distributed in tissues and body fluids involved in various physiological processes [11, 26, 27]. Multiple reports have shown that the cytoplasm sCLU is cytoprotective and anti-apoptotic [28, 29], whereas nCLU protein is proapoptotic. Abnormal oncogenic sCLU expression was reported to correlate closely with HCC progression, such as inducing epithelial-mesenchymal transition (EMT) [30], formation of multiple drug resistance (MDR) [31], distal metastasis of tumor cells, and malignant transformation of hepatocytes, interaction with oncogenes or suppressor genes, and related signal pathways (**Figure 1**) [32, 33]. Because of ischemic or hypoxic microenvironment existence in cancerous tissues, the sCLU are often adaptively over-expressed and closely related with increased tumorigenicity, metastatic potential, and MDR to chemotherapy. As a stress-induced chaperone that inhibits protein misfolding and aggregation in a manner similar to small heat shock proteins (HSPs) [34, 35], its promoter

Oncogenic Secretory Clusterin: A Promising Therapeutic Target for Hepatocellular Carcinoma

http://dx.doi.org/10.5772/intechopen.71007

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**Figure 1.** Potential mechanisms of hepatic sCLU in hepatocellular carcinoma. Cyto C, cytochrome c; ER, endoplasmic reticulum; Gene Reg., gene regulation; HIF-1α, hypoxia inducible factor-1α; IGF, insulin-like factor; MDR, multiple drug resistance; MMP, matrix metalloproteinase; nCLU, nuclear clusterin; NF-κB, nuclear factor-κB; PKC, protein kinase C;

PI3K, phosphatidylinositol 3-kinase; Scr, sarcoma gene; sCLU, secretory clusterin.

Molecular chaperones are proteins that response to cellular stresses including genotoxic agents, nutrient starvation, and heat shock, with cellular stresses-induced protein misfolding, aggregation, and denaturation [10, 11]. To date, only few specific markers such as hepatoma-specific γ-glutamyl transferase [12, 13], oncofetal antigen glypican-3 (GPC-3) [14, 15], hepatoma-specific alpha-fetoprotein (HS-AFP or AFP-L3) [16], member 3a of Wingless-type MMTV integration site family (Wnt3a) [17, 18], and molecular chaperones like heat shock proteins (Hsp27 or Hsp90) [19] and clusterin have been developed as valuable biomarkers for primary hepatocellular carcinoma (PHC) diagnosis and surveillance. The clusterin (CLU) that was first detected in HCC tissues by Tobe et al., who found that SP40-40 gene in hepatoma cells was located in human chromosome 8, also designated as apolipoprotein J (APOJ), SP-40, sulfated glycoprotein 2 (SGP2), and testosterone-repressed prostate message 2 (TRPM2) [20]. Following the detection of their complete cDNA cloning, sequencing and comparison, secretory CLU (sCLU) is found to be the mature isoform of cytoplasm endoplasmic reticulum (ER)-Golgi CLU, which is over-expressed in a wide variety of tumors with oncogenicity [21, 22]. Recently, the mechanisms of abnormal sCLU expression and its targeted effects for HCC have been explored [23, 24]. This article summarizes some progression of sCLU as a promising target for HCC gene therapy.
