Objective Esophageal squamous cell carcinoma (ESCC) is the major histological form of oesophageal cancer in East Asian countries. Despite recent improvements in multimodality treatment, including surgery, radiotherapy and chemotherapy, the prognosis for patients with ESCC remains unsatisfactory. Therefore, development of novel therapy is urgently required. Suppressor of cytokine signaling-1 (SOCS-1) has been cloned as a negative regulator of various cytokine signaling. Recently, lines of evidences suggest that overexpression of SOCS-1 has been considered as a promising therapeutic approach for treatment of cancer. This study was aimed to evaluate the therapeutic effect of the overexpression of SOCS-1 by adenoviral vector (AdSOCS-1) against ESCC.
METHODS By WST-8 assay, cell growth inhibition via infection with various dose of AdSOCS-1 was evaluated in 11 ESCC cell lines in vitro. We also evaluated the induction of apoptosis by overexpression of SOCS-1 in vitro. To evaluate the therapeutic efficacy of AdSOCS-1, ESCC cell line (TE-8) was subcutaneously implanted into the ICR nu/nu mice. In addition, therapeutic efficacy was also assessed using human xenografts subcutaneously transplanted in imuune-deficient mice. Mice were intra-tumorally injection with AdSOCS-1 or control adenovirus vector (AdLacZ) twice a week for 4weeks.
RESULTS Among 11 ESCC cell lines, AdSOCS-1, markedly suppressed proliferation of 8 ESCC cell lines in vitro. AdSOCS-1 strongly induced apoptosis in vitro, via inhibiting JAK/STAT3 pathway. In the TE8 xenograft model, the volume of tumors after therapy in AdSOCS-1 group (1,580 ± 1,005mm3) were lower than that in control group (2,690 ± 1,309mm3). Furthermore, compared with AdLacZ, injection with AdSOCS-1 also inhibited the tumor growth of patient derived ESCC xenografts.
CONCLUSIONS Our results indicated that overexpression of SOCS-1 inhibited the progression of ESCC both in ESCC cell lines and ESCC xenograft model derived from patient. SOCS-1 can be a promising novel therapeutic approach for intra-lesional therapy in ESCC.
Citation Format: Hisashi Hara, Rie Nakatsuka, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Hiroshi Miyata, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Tetsuji Naka. Gene therapy for esophageal squamous cell carcinoma using SOCS-1 expressing adenoviral vector. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4213. doi:10.1158/1538-7445.AM2015-4213