Huang Chuan-Zhong, Huang Ai-Min, Liu Jing-Feng, Wang Bin, Lin Ke-Can, Ye Yun-Bin
Immuno-Oncology Laboratory of Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, China.
Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, China.
Cell Physiol Biochem. 2018;47(6):2340-2349. doi: 10.1159/000491540. Epub 2018 Jul 10.
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a major threat to human health. The condition carries a high risk of death; 45% of new cases occur in China. Surgical resection is the first choice for treatment of HCC, but 30.9% of patients experience recurrence within 6 months after the operation. To improve patient survival, we must determine how to reduce the probability of recurrence and metastasis and elucidate the underlying mechanism of disease. We therefore studied the effect of somatostatin octapeptide (octreotide) on the invasion and metastasis of HCC.
The migration and invasion cytological tests were used to detect the effect of octreotide on liver cancer cells (SK-Hep-1 and HepG2). PEBP1 RNAi was used to knockdown expression. Invasion and metastasis were measured with transwell migration and wound-healing assays. Western blotting was used to detect changes in levels of PEBP1 and invasion pathway proteins after octreotide treatment. The effect of octreotide was studied in vivo by establishing a pulmonary metastasis model using SK-Hep-1 cells in nude mice. In-vivo bioluminescence imaging and hematoxylin and eosin staining of lung tissue were used to verify the results.
Increasing concentrations of octreotide were progressively more effective in halting the invasion and metastasis of liver cancer cells. Octreotide may upregulate PEBP1, TIMP-2, and E-cadherin while downregulating MMP-2 and Twist to inhibit cell invasion and metastasis. And downregulation of PEBP1 would also change the expression of MMP-2, TIMP-2 and Twist. The in-vivo experiments showed no cancer cell metastasis in 4 of the 6 mice in the octreotide-treatment group, while all of the mice in the control group displayed pulmonary metastasis of human HCC cells. And the survival period of the mice in the octreotide-treatment group was significantly prolonged.
Octreotide may weaken invasion and metastasis through the upregulation of PEBP1. Octreotide may reduce the risk of recurrence and metastasis after surgery for liver cancer.
背景/目的：肝细胞癌（HCC）是对人类健康的重大威胁。该疾病具有很高的死亡风险；45%的新发病例发生在中国。手术切除是治疗HCC的首选方法，但30.9%的患者在术后6个月内出现复发。为了提高患者生存率，我们必须确定如何降低复发和转移的概率，并阐明疾病的潜在机制。因此，我们研究了生长抑素八肽（奥曲肽）对HCC侵袭和转移的影响。
采用迁移和侵袭细胞学试验检测奥曲肽对肝癌细胞（SK-Hep-1和HepG2）的作用。使用PEBP1 RNAi敲低表达。通过Transwell迁移和伤口愈合试验测量侵袭和转移情况。采用蛋白质免疫印迹法检测奥曲肽处理后PEBP1和侵袭途径蛋白水平的变化。通过在裸鼠中使用SK-Hep-1细胞建立肺转移模型，在体内研究奥曲肽的作用。采用体内生物发光成像和肺组织苏木精-伊红染色验证结果。
奥曲肽浓度增加对阻止肝癌细胞侵袭和转移的效果逐渐增强。奥曲肽可能上调PEBP1、TIMP-2和E-钙黏蛋白，同时下调MMP-2和Twist以抑制细胞侵袭和转移。并且PEBP1的下调也会改变MMP-2、TIMP-2和Twist的表达。体内实验显示，奥曲肽治疗组6只小鼠中有4只未出现癌细胞转移，而对照组所有小鼠均出现人HCC细胞肺转移。并且奥曲肽治疗组小鼠的生存期明显延长。
奥曲肽可能通过上调PEBP1减弱侵袭和转移。奥曲肽可能降低肝癌手术后复发和转移的风险。
