Survivin promotes cell proliferation in human hepatocellular carcinoma

Abstract

Survivin is a recently described inhibitor of apoptosis. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression and function of survivin in human hepatocellular carcinomas (HCCs). We have shown that 4 HCC cell lines and 7 out of 8 human HCC tissues expressed survivin messenger RNA (mRNA), whereas expression of survivin mRNA was not detected in normal liver and nontumor areas of these tissues using the reverse transcription polymerase chain reaction. Survivin was detected primarily in the nucleus by immunofluorescence staining of HCC cells. In addition, 14 of 20 (70%) HCC tissues showed positive nuclear staining for survivin, whereas nontumor tissues showed little detectable staining by immunohistochemistry. Survivin expression strongly correlated with the proliferation index but not significantly with the apoptosis index in HCC tissues. Therefore, we performed cell cycle analysis after survivin transfection and showed that overexpression of survivin resulted in a decrease in the G 0 /G 1 phase and an increase in the S phase in all 4 HCC cell lines. Furthermore, we have found that survivin interacted with cyclin-dependent kinase 4 (Cdk4) and overexpression of survivin released p21 WAF1/Cip1 (p21) from Cdk4. From these results, we conclude that survivin promotes cell proliferation by interacting with Cdk4 and releasing p21 from Cdk4. This may play an important role in carcinogenesis and progression of human HCCs. (HEPA-TOLOGY 2000;31:1080-1085.)Regulation of programmed cell death is important in the preservation of homeostasis and morphogenesis of human tissues. 1,2 Impairment of apoptosis facilitates the accumulation of gene mutations by prolonging the cell cycle span and promoting resistance to immune-based cytotoxicity, 3 finally contributing to carcinogenesis. 4 It has been shown recently that the inhibitors of apoptosis proteins (IAP) are crucial regulators in the molecular mechanism of apoptosis. [5][6][7] Among the IAP members, survivin is unique in that it is undetectable in normal adult tissue, but abundantly expressed in transformed cells and a variety of human cancers. 8 It has also been shown that survivin inhibits apoptosis in cells exposed to diverse apoptotic stimuli 8-11 by associating with microtubules of the mitotic spindle 9 and inhibiting caspase activity. 10 Expression of survivin is highly correlated with prognosis in patients with neuroblastoma, 7,12 gastric cancer, 13 colorectal cancer, 14 and bladder cancers. 15 However, the biological functions of survivin, other than its antiapoptotic effect, are not well understood in human cancers.Therefore, to gain insight into additional roles of survivin in malignant cells, we investigated the expression and function of survivin in hepatocellular carcinoma (HCC) cell lines and human HCC. In this study, we showed that survivin expression correlates with HCC cell proliferation in the majority of human HCC tissues. Survivin overexpression obliterates the G 1 checkpoint by releasing p21 WAF1/Cip...

Nuclear and cytoplasmic expression of survivin in 67 surgically resected pancreatic cancer patients

“…This evidence could justify the poor prognosis of human cancer with high cytoplasmic Survivin expression (Adida et al, 1998b;Swana et al, 1999;Ito et al, 2000).…”

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

“…The evidence on the molecular mechanism also showed that survivin prompted proliferation of HCC cells. 15 On the one hand, survivin has an important role in the regulation of cell division, however, on the other hand survivin, as a member of the inhibitory apoptosis family, exerts the capability of antiapoptosis and the reduced sensitization of cancer cells to chemotherapy and radiotherapy. 23 Compared with non-HCC cells, HCC cells are more sensitive to the loss of survivin function because of the higher expression of survivin.…”

“…Most importantly, our result was consistent with the results of a previous clinical study that survivin expression in HCC tissues strongly correlated with the proliferation index, but did not significantly correlate with the apoptosis index. 15 A recent study has shown that adenovirus could be a promising delivery system to express anti-survivin hammerhead ribozymes in vivo. 33 In our in vivo study, adenovirus-mediated survivin shRNA was intratumorally injected in nude mice.…”

“…Supportive evidence has suggested that survivin promotes cell proliferation in human HCC both in vitro and in vivo. 15 It has been demonstrated that survivin overexpression in HCC cells obliterates the G1 checkpoint by releasing p21 WAF1/Cip1 from the p21/cyclin-dependent kinase 4 complex and enforces procaspase 3/p21 complex formation to suppress cell death signaling. These observations indicate that survivin may have an important role in the progression of HCCs.…”

Functional analysis of a survivin-like gene in Bombyx mori

“…IAPs, which were first found in baculoviruses, are classified into five types, IAP1 through IAP5, according to their sequence homology (Luque et al 2001). In recent years, svv has been studied in many mammalian species, such as humans, guinea pigs and mice (Ito et al 2000;Habtemichael et al 2010;Stauber et al 2006). Previous studies have shown that svv is abundantly expressed in human cancers but is almost absent from normal differentiated cells (Ambrosini et al 1997).…”