Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress.

Abstract

Asporin (ASPN), a small leucine-rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC-43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC-43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1α and upregulated lactate dehydrogenase A (LDHA) and PDH-E1α, suggesting that ASPN reprograms HSC-43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC-44PE. By contrast, 44As3 cells expressed high levels of HIF1α in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN-/- mice revealed that growth of HSC-43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC-43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1α-mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44-Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas.

• Authors: Yuto Sasaki, Kurara Takagane, Takumi Konno, Go Itoh, Sei Kuriyama, Kazuyoshi Yanagihara, Masakazu Yashiro, Satoru Yamada, Shinya Murakami, Masamitsu Tanaka
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 3 Pg. 1251-1261 (Mar 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33393151 (Publication Type: Journal Article, Observational Study)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• ASPN protein, human
• Aspn protein, mouse
• CD44 protein, human
• Extracellular Matrix Proteins
• HIF1A protein, human
• Hyaluronan Receptors
• Hypoxia-Inducible Factor 1, alpha Subunit
• RAC1 protein, human
• Reactive Oxygen Species
• MMP9 protein, human
• Matrix Metalloproteinase 9
• rac1 GTP-Binding Protein
• Glucose

Topics

• Animals
• Apoptosis
• Cancer-Associated Fibroblasts (cytology, pathology)
• Carcinoma (pathology, surgery)
• Cell Line, Tumor
• Cell Movement
• Extracellular Matrix Proteins (genetics, metabolism)
• Gastrectomy
• Gene Knockdown Techniques
• Glucose (metabolism)
• Humans
• Hyaluronan Receptors (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Knockout
• Mitochondria (pathology)
• Neoplasm Invasiveness (pathology)
• Oxidative Stress
• Reactive Oxygen Species (metabolism)
• Stomach (pathology, surgery)
• Stomach Neoplasms (pathology, surgery)
• Up-Regulation
• Xenograft Model Antitumor Assays
• rac1 GTP-Binding Protein (metabolism)