**3. Biological behaviors of sCLU expression in cancerous tissues**

Although great efforts have been made to explore molecular mechanism of HCC invasion and metastasis in the past decade [39–41], the mechanism of HCC remains incompletely understood. The alterations of sCLU expression at messenger RNA (mRNA) or protein level were investigated in HCC- and their non-tumorous tissues (NT) with self-control [42]. The overall level of sCLU mRNA in the HCC group was 75% up-regulated, 7.5% down-regulated, and 17.5% non-changed. Although no significant difference of the sCLU mRNA level at staging I was found between NT and HCC, they were drastically up-regulated expression from staging II to IV. The staining of sCLU mainly presented in the cytoplasm at protein level in HCC and their NT tissues were analyzed by tissue microarray (TMA) with immunohistochemistry (IHC). Its incidence in the HCC group (73.3%), with 37.5, 68 and 88.9% at staging I, II and III & IV, was significantly higher than that in the NT group (23.3%), respectively. The levels of sCLU protein consistent with their mRNA expression were gradually upregulation with increasing HCC staging [42, 43], indicated that high sCLU should be a valuable biomarker to distinguish malignant from benign liver nodular lesions [44].

The sCLU as a functional homolog of HSPs is a stress-induced chaperone that confers proliferative and closely associates with poor prognosis of HCC. Recurrence and metastasis are the most causes of poor prognosis of HCC. Clinicopathological features of sCLU revealed that its high expression was significantly linked to poor differentiation and advanced TNM stage [45]. There was a trend toward a poorer overall survival in HCC with high sCLU expression. Besides, survival time of HCC with high TNM stage was significantly shorter than that of cases with low stage. Moreover, in the subset of HCC patients with III and IV stage, high sCLU expression was prone to result in a shorter survival time (**Table 1**). There is a closely positive correlation between abnormal sCLU expression and HCC. High sCLU expression has more invasive phenotype for HCC [46]. The upregulation of sCLU is associated with HCC progression by contributing to angiogenesis, chemoresistance, cells survival, and metastasis.

Growing evidences showed that sCLU with molecular chaperones played an important role in MDR formation, cells proliferation, metastasis of HCC [47]. Furthermore, univariate and multivariate analyses indicated that sCLU might be an independent prognostic indicator, in

**Group n Pos. n (%) χ<sup>2</sup>**

AFP (μg /L) ≤50 37 31 (83.78) 1.733 0.118 >50 38 27 (71.05) Portal vein invasion With 7 6 (85.71) 0.309 0.578 Without 68 52 (76.47) HBsAg Negative 46 36 (78.26) 0.058 0.809 Positive 29 22 (75.86) Tumor size ≤5 cm 45 33 (73.33) 1.027 0.311 >5 cm 30 25 (83.33) Liver cirrhosis With 57 45 (78.95) 0.353 0.552 Without 18 13 (72.22) Lymph node metastasis With 23 22 (95.65) 6.351 0.012\* Without 52 36 (69.23) Differentiation Well & moderate 58 43 (74.14) 1.491 0.222 Poor 17 15 (88.24) Gross classification Unifocal 62 46 (74.19) 1.744 0.187 Multifocal 13 12 (92.31) TNM I & II 45 30 (66.67) 7.683 0.021\* III & IV 30 28 (93.33) Child degree A 44 30 (68.18) 5.086 0.024\* B&C 31 29 (90.32) 5 years' survival No 51 43 (84.31) 4.430 0.035\* Yes 24 15 (62.50)

Oncogenic Secretory Clusterin: A Promising Therapeutic Target for Hepatocellular Carcinoma

 **value** *P* **value**

135

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

The observations were in accordance with the early literature showing that upregulation of sCLU-positive expression might be associated with poor clinical outcome in HCC

line with the factor of lymph node metastasis.

Pos. n (%), positive number (%). \*P<0.05

**4. Circulating sCLU as diagnostic marker**

**Table 1.** Clinicopathological features of hepatic sCLU expression in HCC.

Oncogenic Secretory Clusterin: A Promising Therapeutic Target for Hepatocellular Carcinoma http://dx.doi.org/10.5772/intechopen.71007 135


**Table 1.** Clinicopathological features of hepatic sCLU expression in HCC.

region contains an element recognized by heat shock factor 1 (HSF-1) [36]. Cytoplasm sCLUinhibited apoptosis by interacting with activated Bax, and protects HCC cells from ER stressinduced apoptosis through a physical interaction with glucose-regulated prptein78 (GRP78)

Hepatic sCLU has been confirmed that it was physically associated with eukaryotic translation initiation factor 3 subunit I (EIF3I), and might protect EIF3I protein from degradation. A positive correlation was founded between sCLU and EIF3I, and both of their functions might be as a cooperative unit in HCC. The levels of sCLU and EIF3I expression were investigated in HCC using tissue microarray (TMA) and the patients with high EIF3I level exhibited poor prognosis. After silenced EIF3I, Akt phosphorylation was significantly inhibited. The EIF3I-Akt complex could prevent PP2A-mediated dephosphorylation, which in turn led to a constitutive Akt signal activation, suggesting that the CLU-EIF3I complex might prevent EIF3I

degradation, and then contribute to Akt upregulation [33, 38].

134 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment

distinguish malignant from benign liver nodular lesions [44].

**3. Biological behaviors of sCLU expression in cancerous tissues**

Although great efforts have been made to explore molecular mechanism of HCC invasion and metastasis in the past decade [39–41], the mechanism of HCC remains incompletely understood. The alterations of sCLU expression at messenger RNA (mRNA) or protein level were investigated in HCC- and their non-tumorous tissues (NT) with self-control [42]. The overall level of sCLU mRNA in the HCC group was 75% up-regulated, 7.5% down-regulated, and 17.5% non-changed. Although no significant difference of the sCLU mRNA level at staging I was found between NT and HCC, they were drastically up-regulated expression from staging II to IV. The staining of sCLU mainly presented in the cytoplasm at protein level in HCC and their NT tissues were analyzed by tissue microarray (TMA) with immunohistochemistry (IHC). Its incidence in the HCC group (73.3%), with 37.5, 68 and 88.9% at staging I, II and III & IV, was significantly higher than that in the NT group (23.3%), respectively. The levels of sCLU protein consistent with their mRNA expression were gradually upregulation with increasing HCC staging [42, 43], indicated that high sCLU should be a valuable biomarker to

The sCLU as a functional homolog of HSPs is a stress-induced chaperone that confers proliferative and closely associates with poor prognosis of HCC. Recurrence and metastasis are the most causes of poor prognosis of HCC. Clinicopathological features of sCLU revealed that its high expression was significantly linked to poor differentiation and advanced TNM stage [45]. There was a trend toward a poorer overall survival in HCC with high sCLU expression. Besides, survival time of HCC with high TNM stage was significantly shorter than that of cases with low stage. Moreover, in the subset of HCC patients with III and IV stage, high sCLU expression was prone to result in a shorter survival time (**Table 1**). There is a closely positive correlation between abnormal sCLU expression and HCC. High sCLU expression has more invasive phenotype for HCC [46]. The upregulation of sCLU is associated with HCC progression by contributing to angiogenesis, chemoresistance, cells survival, and metastasis.

[29, 37].

Growing evidences showed that sCLU with molecular chaperones played an important role in MDR formation, cells proliferation, metastasis of HCC [47]. Furthermore, univariate and multivariate analyses indicated that sCLU might be an independent prognostic indicator, in line with the factor of lymph node metastasis.
