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GPI-80 增強腫瘤細胞中 NF-κB 的激活

發(fā)表日期：2021-11-15

GPI-80 Augments NF-κB Activation in Tumor Cells

GPI-80 增強腫瘤細胞中 NF-κB 的激活

Recent studies have discovered a relationship between glycosylphosphatidylinositol (GPI)-anchored protein 80 (GPI-80)/VNN2 (80 kDa GPI-anchored protein) and malignant tumors. GPI-80 is known to regulate neutrophil adhesion; however, the action of GPI-80 on tumors is still obscure. In this study, although the expression of GPI-80 mRNA was detectable in several tumor cell lines, the levels of GPI-80 protein were significantly lower than that in neutrophils. To clarify the function of GPI-80 in tumor cells, GPI-80-expressing cells and GPI-80/VNN2 gene-deleted cells were established using PC3 prostate cancer cells. In GPI-80-expressing cells, GPI-80 was mainly detected in vesicles. Furthermore, soluble GPI-80 in the conditioned medium was associated with the exosome marker CD63 and was also detected in the plasma obtained from prostate cancer patients. Unexpectedly, cell adhesion and migration of GPI-80-expressing PC3 cells were not modulated by anti-GPI-80 antibody treatment. However, similar to the GPI-80 family molecule, VNN1, the pantetheinase activity and oxidative state were augmented in GPI-80-expressing cells. GPI-80-expressing cells facilitated non-adhesive proliferation, slow cell proliferation, NF-κB activation and IL-1β production. These phenomena are known to be induced by physiological elevation of the oxidative state. Thus, these observations indicated that GPI-80 affects various tumor responses related to oxidation.

最近的研究發(fā)現(xiàn)了糖基磷脂酰肌醇（GPI）-錨定蛋白80（GPI-80）/VNN2（80 kDa GPI-錨定蛋白）與惡性腫瘤之間的關系。已知 GPI-80 可調節(jié)中性粒細胞粘附；然而，GPI-80 對腫瘤的作用仍不清楚。在這項研究中，雖然在幾種腫瘤細胞系中可檢測到 GPI-80 mRNA 的表達，但 GPI-80 蛋白的水平顯著低于中性粒細胞。為了闡明GPI-80在腫瘤細胞中的功能，使用PC3前列腺癌細胞建立了表達GPI-80的細胞和GPI-80/VNN2基因缺失的細胞。在表達 GPI-80 的細胞中，主要在囊泡中檢測到 GPI-80。此外，條件培養(yǎng)基中的可溶性 GPI-80 與外泌體標志物 CD63 相關，并且也在從前列腺癌患者獲得的血漿中檢測到。出乎意料的是，表達 GPI-80 的 PC3 細胞的細胞粘附和遷移不受抗 GPI-80 抗體處理的調節(jié)。然而，與 GPI-80 家族分子 VNN1 類似，泛酸酶活性和氧化狀態(tài)在表達 GPI-80 的細胞中得到增強。表達 GPI-80 的細胞促進非粘附性增殖、減緩細胞增殖、NF-κB 活化和 IL-1β 產生。已知這些現(xiàn)象是由氧化狀態(tài)的生理升高引起的。因此，這些觀察表明 GPI-80 影響與氧化相關的各種腫瘤反應。表達 GPI-80 的 PC3 細胞的細胞粘附和遷移不受抗 GPI-80 抗體處理的調節(jié)。然而，與 GPI-80 家族分子 VNN1 類似，泛酸酶活性和氧化狀態(tài)在表達 GPI-80 的細胞中得到增強。表達 GPI-80 的細胞促進非粘附性增殖、減緩細胞增殖、NF-κB 活化和 IL-1β 產生。已知這些現(xiàn)象是由氧化狀態(tài)的生理升高引起的。因此，這些觀察表明 GPI-80 影響與氧化相關的各種腫瘤反應。表達 GPI-80 的 PC3 細胞的細胞粘附和遷移不受抗 GPI-80 抗體處理的調節(jié)。然而，與 GPI-80 家族分子 VNN1 類似，泛酸酶活性和氧化狀態(tài)在表達 GPI-80 的細胞中得到增強。表達 GPI-80 的細胞促進非粘附性增殖、減緩細胞增殖、NF-κB 活化和 IL-1β 產生。已知這些現(xiàn)象是由氧化狀態(tài)的生理升高引起的。因此，這些觀察表明 GPI-80 影響與氧化相關的各種腫瘤反應。NF-κB 活化和 IL-1β 產生。已知這些現(xiàn)象是由氧化狀態(tài)的生理升高引起的。因此，這些觀察表明 GPI-80 影響與氧化相關的各種腫瘤反應。NF-κB 活化和 IL-1β 產生。已知這些現(xiàn)象是由氧化狀態(tài)的生理升高引起的。因此，這些觀察表明 GPI-80 影響與氧化相關的各種腫瘤反應。

T175細胞培養(yǎng)瓶

Molecular targeted drugs and immune checkpoint inhibitors have opened a new era of cancer therapy. Recently, clinical studies have focused on the individual differences in therapeutic efficacy as well as the side effects [1]. Although the molecular mechanisms of resistance to these therapies have been elucidated, effective strategies to prevent or treat resistant tumors are nevertheless required to improve clinical outcomes for patients [2]. Therefore, in order to develop effective treatments, investigation into the mechanism of malignant transformation is the need of the hour.

Various comprehensive analytical studies have identified many molecules associated with tumor formation and malignancy. Recently, glycosylphosphatidylinositol (GPI)-anchored protein (GPI-80 also known as VNN2) has been identified as one of the molecules associated with chemotherapeutic resistance of tumors [3]. GPI-80, identified in human neutrophils [4], has been reported to regulate neutrophil adhesion and migration [4]. Furthermore, GPI-80 co-localizes with β2 integrin on resting neutrophils and is concentrated on pseudopodia during neutrophil migration [5]. Based on these observations, GPI-80 is considered to be a molecule that regulates adhesion on neutrophils. However, GPI-80 was detected not only on pseudopods but also in secretory vesicles [6], and soluble GPI-80 is released from activated neutrophils [7]. Besides neutrophils, hematopoietic stem cells also express GPI-80. Therefore, GPI-80 is considered to be a marker for hematopoietic stem cells.

Moreover, it has also been reported that GPI-80 is associated with malignant tumors [8]. In a previous study, microRNA-106a targeted GPI-80 and suppressed its expression. Inhibition of microRNA-106a induced overexpression of GPI-80 leading to reduced proliferation of osteosarcoma cells and increased apoptosis. This result suggested that GPI-80 might reduce osteosarcoma tumorigenesis. However, it has been reported that GPI-80 mRNA expression was upregulated in androgen-deprived prostate cancer cells (PC3 cells) [9] as well as in the metastatic human esophageal squamous cell carcinoma cell line (T.Tn-AT1 cells) [10]. These observations suggest that increased levels of GPI-80 may be involved in tumor growth and metastasis.

GPI-80 is a member of the pantetheinase gene family that consists of pantetheinase/VNN1, which produces pantothenic acid (vitamin B5) and cysteamine from pantetheine [11]. VNN1 is thought to limit the Warburg effect and suppress the growth of sarcomas [12]. It is still uncertain whether GPI-80 exhibits pantetheinase activity.

The present study examines the role of GPI-80 in tumor cells by overexpressing GPI-80 as well as deleting GPI-80 in PC3 cells. This study demonstrates the basic mechanism of action of GPI-80 in tumors.

40層細胞工廠

分子靶向藥物和免疫檢查點抑制劑開啟了癌癥治療的新時代。最近，臨床研究集中在治療效果和副作用的個體差異[ 1 ]。盡管已經闡明了對這些療法產生耐藥性的分子機制，但仍需要預防或治療耐藥性腫瘤的有效策略來改善患者的臨床結果 [ 2 ]。因此，為了開發(fā)有效的治療方法，研究惡變的機制是當務之急。

各種綜合分析研究已經確定了許多與腫瘤形成和惡性腫瘤相關的分子。最近，糖基磷脂酰肌醇 (GPI) 錨定蛋白 (GPI-80 也稱為 VNN2) 已被確定為與腫瘤化療耐藥相關的分子之一 [ 3 ]。GPI-80，在人類中性粒細胞中鑒定 [ 4 ]，據報道可調節(jié)中性粒細胞粘附和遷移 [ 4 ]。此外，GPI-80 與 β2 整合素共定位于靜息中性粒細胞上，并在中性粒細胞遷移過程中集中在偽足上 [ 5]]?；谶@些觀察，GPI-80 被認為是一種調節(jié)嗜中性粒細胞粘附的分子。然而，不僅在偽足上檢測到 GPI-80，還在分泌囊泡中檢測到 GPI-80 [ 6 ]，并且可溶性 GPI-80 從活化的中性粒細胞中釋放出來 [ 7 ]。除了中性粒細胞，造血干細胞也表達 GPI-80。因此，GPI-80被認為是造血干細胞的標志物。

此外，也有報道稱 GPI-80 與惡性腫瘤有關 [ 8 ]。在之前的一項研究中，microRNA-106a 靶向 GPI-80 并抑制其表達。microRNA-106a 的抑制誘導 GPI-80 的過度表達，導致骨肉瘤細胞增殖減少和細胞凋亡增加。該結果表明 GPI-80 可能減少骨肉瘤的腫瘤發(fā)生。然而，據報道 GPI-80 mRNA 表達在雄激素剝奪的前列腺癌細胞（PC3 細胞）[ 9 ] 以及轉移性人食管鱗狀細胞癌細胞系（T.Tn-AT1 細胞）中上調[ 9 ]。10 ]。這些觀察結果表明 GPI-80 水平升高可能與腫瘤生長和轉移有關。