Published online Jul 7, 2019. doi: 10.3748/wjg.v25.i25.3196
Peer-review started: February 23, 2019
First decision: April 4, 2019
Revised: May 14, 2019
Accepted: May 31, 2019
Article in press: June 1, 2019
Published online: July 7, 2019
Colorectal cancer (CRC) is the third most common malignancy of the digestive tract and the fifth leading cause of cancer-related mortality in China. Sporamin, a Kunitz-type trypsin inhibitor isolated from sweet potato, is a potential anti-cancer agent with activities against a number of malignant tumor cells in vitro. The liver secretes a myriad of endocrine factors that may facilitate the growth and transformation of tumors in the development of CRC.
To investigate the effects of sporamin on liver morphology and biomarkers of xenografted CRC in the liver of athymic BALB/c mice.
Twenty-seven male BALB/c nude mice were randomly divided into control, vehicle, and sporamin groups. Mice in the latter two groups were intraperitoneally xenografted with LoVo colorectal carcinoma cells and intragastrically infused with saline or sporamin (0.5 g/kg body weight/d), respectively, for 3 wk. Hematoxylin and eosin (HE) staining of the sections was performed to observe morphological changes in hepatic tissue and real-time fluorescent quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to measure the expression of β-catenin and vascular endothelial growth factor (VEGF) in the liver.
Sporamin significantly reduced the number and weight of tumor nodules formed in the abdominal cavity. Compared with the vehicle group, the mean tumor weight (± SD) in the sporamin group was significantly reduced (0.44 ± 0.10 g vs 0.26 ± 0.15 g) and the total number of tumors decreased from 93 to 55. HE staining showed that enlargement of the nucleus and synthesis of proteins within hepatocytes, as well as infiltration of inflammatory cells into the liver, were attenuated by sporamin. Immunohistochemical staining and ELISA showed that the concentrations of β-catenin and VEGF in the liver were significantly reduced by sporamin. Compared with the vehicle group, the expression of β-catenin measured in integrated optical density units per area was reduced in the sporamin group (47.29 ± 9.10 vs 26.14 ± 1.72; P = 0.003). Expression of VEGF was also reduced after sporamin intervention from 20.78 ± 2.06 in the vehicle group to 15.80 ± 1.09 in the sporamin group (P = 0.021). Compared with the vehicle group, the concentration of β-catenin decreased from 134.42 ± 22.04 pg/mL to 109.07 ± 9.65 pg/mL after sporamin intervention (P = 0.00002). qPCR indicated that compared to the vehicle group, relative mRNA expression of β-catenin and VEGF in the liver of mice in the sporamin-treated group was significantly reduced to 71% ± 1% (P = 0.000001) and 23% ± 7% (P = 0.00002), respectively, of the vehicle group levels.
Sporamin down-regulates the expression and secretion of β-catenin and VEGF in the liver, which subsequently inhibits the transcription of downstream genes involved in cancer progression and angiogenesis.
Core tip: Sporamin, a Kunitz-type trypsin inhibitor, restrains the growth of intraperitoneally xenografted LoVo [also known as colorectal cancer (CRC) cells] in athymic BALB/c mice. The mechanism determined by changes in morphology and tumor biomarkers in the liver involves sporamin-induced down-regulation of β-catenin secretion and vascular endothelial growth factor expression. This suppresses the formation of xenografted tumor nodules in vivo and subsequently inhibits the transcription of downstream genes involved in cancer progression and angiogenesis. The anti-cancer effects of sporamin against CRC are closely associated with its inhibitory effect on these tumor biomarkers. Further studies are warranted to elucidate the corresponding signal transduction events that mediate this process.