Annexin�A2 regulates glioma cell proliferation through the STAT3‑cyclin�D1 pathway

Abstract

Annexin A2 (ANXA2) acts as a calcium-dependent phospholipid-binding protein that is widely expressed in vertebrate cells and has abnormally high expression in various tumor cells. However, the detailed molecular mechanism underlying the effects of ANXA2 on glioma cells remains unclear. The present study aimed to investigate the role and underlying molecular mechanisms of ANXA2 in glioma cell proliferation. The results revealed that knockdown of ANXA2 inhibited the proliferation of U251 and U87 glioma cell lines and decreased phosphorylated (p) signal transducer and activator of transcription 3 (STAT3) (Y705) and cyclin D1 expression, leading to impedance of the G 1 -to-S phase transition. Furthermore, it was suggested that ANXA2 may regulate pSTAT3 (Y705) levels through direct binding with STAT3, thereby affecting STAT3-cyclin D1 pathway-mediated cell proliferation. When ANXA2 was re-expressed in ANXA2-knockdown cells, the expression of pSTAT3 (Y705) and cyclin D1 was restored. Furthermore, overexpression of ANXA2 significantly promoted the proliferation of U251 cells, as determined by an MTT assay and a tumor formation assay in nude mice, but had no statistically significant effect on colony formation rate, cell cycle progression or the STAT3-cyclin D1 pathway, suggesting that endogenous ANXA2 may be redundant. Additionally, the present study provided evidence that the overexpression of ANXA2 enhanced the expression of pSTAT3 (Y705) in the presence of epidermal growth factor (EGF), indicating that the proliferation-promoting effect of ANXA2 may be due to the accumulation and synergistic effect of paracrine EGF. Taken together, the present results indicated that ANXA2 may affect the proliferation of human glioma cells through the STAT3-cyclin D1 pathway via direct interaction with STAT3 in U251 and U87 glioma cells. ANXA2 was redundant in this pathway, but positive synergy was revealed to exist between ANXA2 and EGF.

Overexpression of Annexin A2 Promotes Proliferation by Forming a Glypican 1 / c-Myc Positive Feedback Loop: Prognostic Significance in Human Glioma

“…Furthermore, we demonstrated that the overexpression of ANXA2 could obviously increased the proliferation of U118 glioma cells, which expresses higher level of endogenous ANXA2 than normal human astrocyte cell line NHA (data not shown). Similar ndings have been reported in U251 glioma cells and primary patients-derived glioblastoma cells [28,37]. Collectively, these studies support the contribution of ANXA2 to promoted proliferation of glioma cells and the overexpression of ANXA2 was enough to further increase the proliferation ability of glioma cells, which already expressed high levels of exogenous ANXA2.…”

“…Previous studies have suggested that ANXA2 was a crucial protein involved in the over-proliferation of various human malignant tumor cells [26,27,35,36] including glioma cells [37][38][39]. There is evidence that knockdown of ANXA2 inhibited the proliferation of glioma cell lines U251, U87 and GP1 [37,38], primary glioma cells [28,39] and glioblastoma stem-like cells [28,39].…”

“…It has been demonstrated that ANXA2 regulated OSMR expression via STAT3 phosphorylation, resulting in the shift of glioblastoma cells towards a mesenchymal phenotype with prominent proliferation capability [28]. Chen et al reported that ANXA2 knockdown led to a reduction in phosphorylated STAT3 (Y705) through direct binding with STAT3 and suppression of STAT3-cyclin D1 pathway-mediated cell proliferation, which nevertheless could not be activated by ANXA2 overexpression [37]. In our present data, both ANXA2 knockdown and overexpression in uenced the level of c-Myc, and then changed the cell proliferation in U118 cells.…”

The Long Non-coding RNA LINC01133 Promotes Hepatocellular Carcinoma Progression by Sponging miR-199a-5p and Activating Annexin A2

“…Several studies demonstrated that Tyr23 phosphorylation of ANXA2 involves enhancing cancer proliferation and metastasis [38,39]. ANXA2 also regulates glioma cell proliferation via the STAT3-cyclinD1 pathway [40].…”

Versatile role of curcumin and its derivatives in lung cancer therapy

“…It is held that curcumin (1, 2, and 4 hr for 1–12 hr) downregulates the expression of the STAT3 signaling pathway (>50% decrease in expression) in a dose‐dependent manner to inhibit colony formation and cell growth, and induce cell cycle arrest (Feng et al, 2017). Several downstream targets of STAT3 including VEGF, Bcl‐2, and cyclin D1 mediate the stimulatory impact of STAT3 on invasion and proliferation of cancer cells (X. Chen et al, 2019; L. Chen, Lin, Xian, & Zheng, 2019; A. Singh et al, 2019). Curcumin has demonstrated a great potential in inhibition of STAT3 and its downstream targets in both in vitro and in vivo experiments.…”