Inhibition of Growth and Metastasis of Human Hepatocellular Carcinoma by Antisense Oligonucleotide Targeting Signal Transducer and Activator of Transcription 3

Abstract

Purpose: Hepatocellular carcinoma (HCC) is an aggressive malignancy and is a devastating clinical complication of chronic liver disease. Therapeutic options are limited mainly because the genetic and biochemical understanding of this disease remains fragmented.We intended to study the role of signal transducer and activator of transcription 3 (STAT3) aberrant signaling in HCC malignancy, and the therapeutic potential of inhibition of STAT3 expression for HCC. Experimental Design: A 2 ¶-O-methoxyethylribose^modified phosphorothioate antisense oligonucleotide (ASO) was used to knock down STAT3 expression in different human HCC cell lines, including the highly metastatic HCCLM3 derived from orthotopic implantation and subsequent lung metastasis in athymic mice. The effects of STAT3 ASO treatment on HCC cells, metastasis, and animal survival following HCCLM3 orthotopic implantation were evaluated. Results: Specific suppression of phosphorylated STAT3 reduced its DNA-binding activity, inhibited the expression of vascular endothelial growth factor, survivin, matrix metalloproteinases 2 and 9, reduced cell proliferation and migratory potential, induced apoptosis in vitro, and inhibited intradermal angiogenesis and s.c. tumorigenesis upon injection in mice. In mice bearing orthotopically implanted HCCLM3, STAT3 inhibition following therapeutic treatment with STAT3 ASO reduced circulating vascular endothelial growth factor and basic fibroblast growth factor, decreased intratumor CD34-positive microvessel density, intrahepatic and intraperitoneal transmission, and lung metastasis. HCC tumor volume and weight were reduced and the survival time of mice bearing orthotopically xenografted HCC was approximately doubled in STAT3 ASO^treated mice (P < 0.05).Conclusions: Constitutively activated STAT3 is essential for the growth, survival, and metastasis of HCC, suggesting that STAT3-targeted therapy may have utility for HCC.

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

“…Recent studies have also linked Stat3 to metastatic progression in several different cancers, including prostate, lung, ovary, and gastrointestinal tract (16,18,(20)(21)(22). The influence of Stat3 on the metastatic potential of these cancers occurs through a variety of molecular mechanisms (35,(38)(39)(40). This study investigated the immunohistochemical staining of pStat3 in tissue samples of 70 patients with chordoma and sought to establish a relationship between expression and outcome.…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…In all cases, inhibition of persistent STAT3 signaling suppressed the transformed phenotype and tumor progression. Constitutive activation of STAT3 has been frequently detected in clinical incidences of HCC and in more than 50% of human HCC cell lines but not in normal or non-transformed liver cells [179,180,195]. For example, STAT3 was found to be over expressed in proteome microarray analysis of primary HCC [196].…”

“…This is surprising, since rapid activation of the STAT3 transcriptional complex has been reported in the regenerating liver following partial hepatectomy [199]. Also, STAT3 antisense oligonucleotide has been reported to significantly reduce the amount of STAT3 protein and inhibit cell proliferation and tumorigenic growth of several human HCC cell lines transplanted into mice [195]. Activating mutations in the gene encoding the gp130 signaling subunit of IL-6 receptor family members have been identified in benign hepatic adenomas [200].…”

“…When anti-cancer small molecule S3I-201 was administered at a dose of 5 mg/kg every other day to xenografts of the human HCC cell line HUH-7, it was found that S3I-201 inhibited STAT3 tyrosine phosphorylation and tumor growth [6]. The amelioration of the malignant behaviors of HCCLM3 following orthotopic implantation, included impeded migration, hampered neovascularization, inhibited local metastasis, and reduced lung metastasis, indicating that STAT3 also mediates the metastatic potential of HCCLM3, a highly malignant variant of HCC [195].…”

“…Recent studies have linked STAT3 to metastatic progression of liver cancer [195]. Contribution of STAT3 to metastatic progression of liver cancers occurs through a variety of molecular mechanisms [53].…”