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STC2 Is Upregulated in Hepatocellular Carcinoma and Promotes Cell Proliferation and Migration in Vitro

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STC2 Is Upregulated in Hepatocellular Carcinoma and Promotes Cell Proliferation and Migration in Vitro BMB Reports STC2 is upregulated in hepatocellular carcinoma and promotes cell proliferation and migration in vitro Haixiao Wang1,4,#, Kuangjie Wu1,#, Yuan Sun5, Yandong Li2,3, Mingyu Wu1, Qian Qiao1, Yuanjiang Wei1, Ze-Guang Han2,3,* & Bing Cai1,* 1Department of Hepatobiliary Surgery, Wuxi People's Hospital of Nanjing Medical University, Jiangsu, 2Chinese National Human Genome Center, Rui-Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 3Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 4Department of General Surgery, Huaian No. 1 People's Hospital Affiliated to Nanjing Medical University, Huaian, Jiangsu Province, 5Department of Pharmacy, Huaian No. 1 People's Hospital Affiliated to Nanjing Medical University, Huaian, Jiangsu Province, China The human glycoprotein, stanniocalcin 2 (STC2) plays multiple and aflatoxin intake are the most common etiologies for the de- roles in several tumor types, however, its function and clinical velopment of HCC. In recent years, advances in therapeutic mo- significance in hepatocellular carcinoma (HCC) remain unclear. dalities and strategies have improved the chance of curative In this study, we detected STC2 expression by quantitative treatment for HCC. Liver transplantation and surgical resection real-time PCR and found STC2 was upregulated in HCC tissues, are regarded as the main therapeutic treatment after considering correlated with tumor size and multiplicity of HCC. Ectopic tumor extent and hepatic functional reserve (3). And molecular expression of STC2 markedly promoted HCC cell proliferation targeted chemotherapy such as sorafenib and monoclonal anti- and colony formation, while silencing of endogenous STC2 bodies can also significantly improve the long-term survival of resulted in a reduced cell growth by cell cycle delay in G0/G1 HCC patients (4). Because the genetic heterogeneity of different phase. Western blot analysis demonstrated that STC2 could patients affect their response to chemotherapy and the limits of regulate the expression of cyclin D1 and activate extracellular other therapies exist, the HCC patients’ long-term prognosis is signal-regulated kinase 1/2 (ERK1/2) in a dominant-positive still poor for the metastasis and the frequent recurrence (4, 5). manner. Transwell chamber assay also indicated altered patterns During HCC tumorigenesis and progression, specific alter- of STC2 expression had an important effect on cell migration. ations in oncogenes and tumor suppressor-genes are required (6, Our findings suggest that STC2 functions as a potential 7). Hence identifying novel oncogenes as HCC therapeutic oncoprotein in the development and progression of HCC as well agents is a focal point of anti-cancer research. Stanniocalcin as a promising molecular target for HCC therapy. [BMB Reports (STC) is a family of secreted glycoprotein hormones that origi- 2012; 45(11): 629-634] nally discovered in the corpuscles of Stannius, an endocrine gland of fish (8, 9). STC1 and STC2, two homologues of STC family, are reported to involve in calcium and phosphate homeo- INTRODUCTION stasis (10, 11). Both two proteins differ at C-terminal half but share similar hydropathy profiles at the N-terminal half (12). Hepatocellular carcinoma (HCC) is a highly virulent malignancy STC1 is the first discovered Stanniocalcin family member and and its incidence has increased rapidly during the past few deca- has been implicated to participate in different physiological func- des worldwide, with only 9% of patients surviving more than 5 tions (13, 14). STC2 is widely expressed in human tissues with years (1, 2). About half of the cases and deaths are estimated to high transcripts levels in skeletal muscle, heart and pancreas (12, occur in China. Hepatitis B or C viral infection, alcohol abuse 15). Several reports have revealed that STC2 overexpression could promote tumor cell proliferation, invasion and metastasis in prostate cancer, ovarian cancer or neuroblastoma (16-18). *Corresponding authors. Bing Cai, Tel: +86-510-85351093; Fax: STC2 is also vital for cytoprotective properties when exposed to +86-510-82706950; E-mail: [email protected]; Ze-Guang Han, ER stress and hypoxia (19, 20). Although STC2 is well-known in Tel: +86-21-50801325; Fax: +86-21-50800402; E-mail: hanzg@ other tumor types, the relationship between STC2 and HCC has chgc.sh.cn #Haixiao Wang and Kuangjie Wu contributed equally to this work. not yet been reported so far. http://dx.doi.org/10.5483/BMBRep.2012.45.11.086 In this current study, we examined the expression pattern of STC2 in HCC specimens and cell lines, and analyzed the poten- Received 26 April 2012, Revised 14 May 2012, Accepted 6 June 2012 tial correlation between STC2 and HCC. In addition, we also tested its effect on cell proliferation and migration, and inves- Keywords: Cell migration, Cell proliferation, Hepatocellular carci- tigated the potential role of STC2 on HCC cell cycle transition. noma, Stanniocalcin 2 Copyright ⓒ 2012 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/li- censes/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. STC2 is upregulated in hepatocellular carcinoma and promotes cell proliferation and migration in vitro Haixiao Wang, et al. Fig. 1. Expression pattern of STC2 in HCC specimens and cell lines. (A, B) The mRNA expression levels of STC2 in 44 paired HCCs and non-HCCs were determined by quantitative real-time PCR and normal- ized by 2-△Ct method, where β-actin was used as internal control. Compared with noncancerous tissues, the mRNA level of STC2 was significantly higher in 79.5% HCC specimens. The mean ratios of STC2 mRNA levels in HCC tissues to those in paired paratumor tissues (T/N) in each case were calculated and showed by a column. (C) The protein levels of STC2 in 8 matched HCC specimens were analyzed by west- ern blotting. β-actin was used as loading reference. (D) The relative expression lev- els of STC2 in HCC cell lines were eval- uated by Western blotting. ***P ＜ 0.0001. Finally, we explored the underlying mechanism of STC2 func- tions in HCC. Therefore, the data strongly indicated that STC2 might represent as a promising novel therapeutic target for HCC. RESULTS STC2 is frequently upregulated in HCC To evaluate the expression pattern of STC2 in HCC tissues, we performed quantitative real-time PCR approach in 44 pairs of HCCs and non-HCCs. The results indicated that STC2 was sig- nificantly upregulated in HCCs compared with the paired non-HCC tissues (Fig. 1A, P ＜ 0.0001). Among the 44 pairs of clinical samples, 35/44 (79.5%) showed STC2 upregulation (T/N ≥ 1.5), 21/44 (47.7%) (T/N ≥ 5) had severe STC2 increase. 7/44 (15.9%) had no difference (1.5 ＞ T/N ≥ 1), and 2/44 (4.5%) was downregulated (1 ＞ T/N ≥ 0.5) (Fig. 1B). Moreover, Fig. 2. STC2 overexpression promotes HCC cell proliferation and colony total proteins were extracted from random 8 paired HCCs and formation. (A) Exogenous STC2 was expressed in YY-8103 cells trans- paratumor tissues. The protein expression of STC2 was de- fected with the pcDNA3.1-STC2. Parallel cells transfected with empty termined by western blot using a polyclonal antibody to STC2. vector were used as a control. (B) STC2 overexpression promoted cell 7/8 (87.5%) were significantly elevated in HCCs than paired proliferation of YY-8103 cells. (C) Ectopic STC2 expression enhanced the colony formation ability of YY-8103 cells. The histogram represents non-HCC tissues in line with the quantitative real-time PCR re- the mean colony number of 3 independent experiments (mean ± SD). sults (Fig. 1C). *P ＜ 0.05 and **P ＜ 0.01. Subsequently, we accessed the correlation between STC2 ex- pression and clinicopathological characteristics in HCC. The re- sults demonstrated STC2 mRNA levels were higher in samples not significantly related to the upregulation of STC2 (Supplemen- with diameter of tumor ≥ 5 cm than those ＜ 5 cm，and in tal Table 1, P ＞ 0.05). In addition, we measured the protein ex- samples with multiple tumors than those with a single tumor pression level of STC2 in available 8 HCC cell lines by western (Supplemental Table 1, P ＜ 0.05). Furthermore, it was trend to blot analysis. The results showed that STC2 level was higher in be associated with the high TNM staging (I/II vs III/IV) of HCC MHCC-97H, MHCC-97L and MHCC-LM6 cells, which all pos- (Supplemental Table 1, P=0.063). Other clinicopathologic pa- sess high metastatic potential (Fig. 1D). Taken together, the ex- rameters, such as sex, patient age (≤50 years vs ＞50 years), pression pattern of STC2 in clinical samples and cell lines sug- HBsAg, liver cirrhosis, Child-Pugh score, serum AFP, tumor dif- gested it may play an important role in the pathogenesis of HCC. ferentiation, tumor encapsulation and microvascular invasion are 630 BMB Reports http://bmbreports.org STC2 is upregulated in hepatocellular carcinoma and promotes cell proliferation and migration in vitro Haixiao Wang, et al. Fig. 3. STC2 silencing suppresses cell growth and induces cell cycle delay in HCC cells. (A) The specific siRNA for STC2 and control siRNA were transiently transfected into MHCC-97H and MHCC- 97L cells. The RNAi efficiency was demonstrated by quantitative real-time PCR, where si-NC was used as control. (B) STC2 depletion by siRNA dramat- ically inhibited cell proliferation in both MHCC-97H and MHCC-97L cells using cell viability assay. (C) The pSUPER- shRNA against STC2 significantly knocked down the endogenous STC2 mRNA expression. (D) STC2 knockdown by shRNA reduced the col- ony formation, as shown by representative dishes of colony formation of those cells trans- fected with pSUPER- shSTC2 (right) and vec- tor used as control (left).
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