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.

Cancer‐associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T‐cell suppression

“…Taken together, these data suggest that the features of CEFs evaluated in this study were unlikely to have been induced by TGF- CEFs induced cancer cell spreading via IL-1 secretion, which activates Rac1 in cancer cells. Moreover, ASPN upregulates CD44 expression and activates Rac1 via interaction with CD44 on the cell membrane [16,33], which also increases cancer cell spreading (Fig. 7A).…”

“…As a downstream target of NF-B signaling, ASPN is upregulated because its promoter contains a binding site for NF-B p65 [41]. In turn, ASPN further increases NF-B and HIF-1 expression [33] (Fig 7A). Therefore, ROS production is a major trigger of the inflammatory response in CEFs.…”

“…*COX2 expression is known to be upregulated by NS-398 as a feedback mechanism [52]. [ 16,33], which also increases cancer cell spreading (Fig. 7A).…”

Asporin Is Highly Expressed in CAFs of High Grade Serous Ovarian Cancinoma Patients and Predicts Poor Prognosis

“…The earlier study found that Asporin played an important role in osteoarthritis, rheumatoid arthritis and lumbar disc degeneration and other bone and joint diseases by affecting the formation and differentiation of bone and cartilage [17][18]. Recently, some studies have con rmed that Asporin is secreted by CAFs and can promote the invasion of tumor cells by binding with CD44 receptor in a variety of human cancers [13,[19][20]. Those studies suggest that Asporin could be a new potential target for human cancer treatment targeting the tumor microenvironment.…”

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma

“…Whether SFN diminishes CD44s in parallel and whether SFN action on CD44 correlates with oxidative stress requires further investigation. Sasaki’s work has indicated a close interaction between CD44s and HIF1α-mediated resistance to oxidative stress [ 153 ], and Xu et al have shown that reduced CD44s expression correlates with induced intracellular levels of ROS in bladder cancer cells [ 154 ]. It seems likely, therefore, that SFN’s action on CD44 expression is linked to ROS and ROS-related pathways.…”