RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells.

Abstract

BACKGROUND:

ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo.

METHODS:

Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot.

RESULTS:

ST6GalNAc I siRNA inhibited gastric cancer cell growth, migration, and invasion in vitro. Furthermore, intraperitoneal administration of ST6GalNAc I siRNA- liposome significantly inhibited peritoneal dissemination and prolonged the survival of xenograft model mice with peritoneal dissemination of gastric cancer. PCR array confirmed that suppression of ST6GalNAc I caused a significant reduction in expression of IGF-1 mRNA. Decreased IGF-1 expression in MKN45 cells treated with ST6GalNAc I siRNA was accompanied by reduced phosphorylation of STAT5b.

CONCLUSION:

ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer.

• Authors: Fumito Tamura, Yasushi Sato, Masahiro Hirakawa, Makoto Yoshida, Michihiro Ono, Takahiro Osuga, Yutaka Okagawa, Naoki Uemura, Yohei Arihara, Kazuyuki Murase, Yutaka Kawano, Satoshi Iyama, Kohichi Takada, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato
• Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 19 Issue 1 Pg. 85-97 (Jan 2016) ISSN: 1436-3305 [Electronic] Japan
• PMID: 25532910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Tumor-Associated, Carbohydrate
• STAT5 Transcription Factor
• STAT5B protein, human
• sialosyl-Tn antigen
• Insulin-Like Growth Factor I
• Sialyltransferases
• CMP-N-acetylneuraminate-alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase

Topics

• Animals
• Antigens, Tumor-Associated, Carbohydrate (metabolism)
• Cell Line, Tumor
• Cell Movement (genetics)
• Female
• Gene Expression Regulation, Enzymologic
• Gene Silencing
• Humans
• Insulin-Like Growth Factor I (genetics, metabolism)
• Mice, Inbred BALB C
• Peritoneal Neoplasms (secondary)
• RNA Interference
• STAT5 Transcription Factor (metabolism)
• Sialyltransferases (genetics, metabolism)
• Stomach Neoplasms (enzymology, mortality, pathology)
• Xenograft Model Antitumor Assays