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首页> 外文期刊>Molecular Cancer >CD98hc (SLC3A2) drives integrin-dependent renal cancer cell behavior
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CD98hc (SLC3A2) drives integrin-dependent renal cancer cell behavior

机译：CD98hc（SLC3A2）驱动整合素依赖性肾癌细胞的行为

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Background Overexpression of CD98hc (SLC3A2) occurs in a variety of cancers and is suspected to contribute to tumor growth. CD98, a heterodimeric transmembrane protein, physically associates with certain integrin β subunit cytoplasmic domains via its heavy chain, CD98hc. CD98hc regulates adhesion-induced intracellular signal transduction via integrins, thereby, affecting cell proliferation and clonal expansion. Disruption of CD98hc led to embryonic lethality in mice (E 3.5 and E 9.5) and CD98hc ?/? embryonic stem cell transplantation failed to form teratomas, while CD98hc over-expression in somatic cells resulted in anchorage-independent growth. However, it is unclear whether interference with CD98hc expression tumor cell behavior. Methods Renal cell cancer cell lines have been used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometric analysis was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to stably knockdown or reconstitute full length or mutated CD98hc. The role of CD98 as a promotor of tumorigenesis was evaluated using an in in vivo tumor transplantation animal model. Immunohistochemical analysis was performed to analyze cell proliferation and CD98 expression in tumors. Results This report shows that CD98hc silencing in clear cell renal cancer cells reverts certain characteristics of tumorigenesis, including cell spreading, migration, proliferation and survival in vitro , and tumor growth in vivo . Acquisition of tumorigenic characteristics in clear cell renal cancer cells occurred through the integrin binding domain of CD98hc. A CD98hc/integrin interaction was required for adhesion-induced sustained FAK phosphorylation and activation of the major downstream signaling pathways PI3k/Akt and MEK/ERK, while overexpression of a constitutive active form of FAK rescued the CD98hc deficiency. Conclusions In this study we demonstrate that loss of CD98hc blocks tumorigenic potential in renal cell cancer.
机译：背景CD98hc（SLC3A2）的过度表达发生在多种癌症中，并被怀疑会导致肿瘤的生长。 CD98是一种异二聚体跨膜蛋白，通过其重链CD98hc与某些整联蛋白β亚基胞质域发生物理关联。 CD98hc通过整联蛋白调节粘附诱导的细胞内信号转导，从而影响细胞增殖和克隆扩增。 CD98hc的破坏导致小鼠（E 3.5和E 9.5）和CD98hc的致死性。胚胎干细胞移植未能形成畸胎瘤，而体细胞中CD98hc的过表达导致锚定非依赖性生长。但是，尚不清楚是否干扰CD98hc表达肿瘤细胞的行为。方法已通过细胞粘附，细胞迁移和细胞扩散试验，使用肾癌细胞系来确定CD98hc表达对癌细胞行为的影响。进行流式细胞术分析以研究脱离或血清饥饿后的细胞凋亡率。 shRNA-慢病毒构建体用于稳定敲低或重组全长或突变的CD98hc。使用体内肿瘤移植动物模型评估了CD98作为肿瘤发生促进剂的作用。进行免疫组织化学分析以分析肿瘤中的细胞增殖和CD98表达。结果该报告表明，在透明细胞肾癌细胞中CD98hc沉默可恢复某些肿瘤发生特征，包括体外细胞扩散，迁移，增殖和存活以及体内肿瘤生长。通过CD98hc的整联蛋白结合结构域获得了在透明细胞肾癌细胞中的致瘤特性。粘附诱导的持续FAK磷酸化和主要下游信号传导通路PI3k / Akt和MEK / ERK的激活需要CD98hc /整联蛋白相互作用，而FAK的组成型活性形式的过表达可以挽救CD98hc的缺乏。结论在这项研究中，我们证明了CD98hc的丧失可阻断肾细胞癌的致瘤潜力。

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