The exon 38-containing ARHGEF11 splice isoform is differentially expressed and is required for migration and growth in invasive breast cancer cells.
The exon 38-containing ARHGEF11 splice isoform is differentially expressed and is required for migration and growth in invasive breast cancer cells.
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DOI：
10.18632/oncotarget.20985
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发表时间：
2017-11-03
期刊：
影响因子：
--
通讯作者：
Sugimoto H
中科院分区：
文献类型：
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作者：
Itoh M;Radisky DC;Hashiguchi M;Sugimoto H
乳腺癌侵袭涉及细胞间连接的丧失和侵袭性迁移表型的获得，基底固有亚型的乳腺癌细胞比其他亚型的乳腺癌细胞更具侵袭性和转移性。ARHGEF11是一种RhoGEF，先前已被证明与周结肌动球蛋白环（PJAR）上的紧密连接蛋白ZO-1结合，PJAR是一个皮质组织的肌动蛋白和肌动蛋白丝网络，与调节细胞-细胞粘附和极化的连接复合物有关。我们在这里表明，ARHGEF11显示剪接异构体表达根据乳腺癌细胞的内在亚型而不同，并控制其侵袭性表型。腔内亚型乳腺癌细胞表达缺乏38（38-）外显子的ARHGEF11亚型，该亚型在PJAR上与ZO-1结合，是形成和维持细胞-细胞连接所必需的。基底亚型乳腺癌细胞表达含有38（38+）外显子的ARHGEF11亚型，该亚型不与ZO-1结合，并驱动细胞迁移和运动。在基底亚型乳腺癌细胞中，ARHGEF11的缺失足以改变细胞形态，使细胞从具有广泛细胞突起的间充质星状形态转变为鹅卵石样上皮形态，并抑制体外和体内的生长和存活。这些发现表明，ARHGEF11特定剪接异构体的表达与乳腺癌细胞的恶性表型密切相关，将ARHGEF11外显子38（+）确定为乳腺癌治疗的生物标志物和靶点。
Breast cancer invasion involves the loss of cell-cell junctions and acquisition of an invasive, migratory phenotype, and breast cancer cells of the basal intrinsic subtype are more invasive and metastatic than breast cancer cells of other subtypes. ARHGEF11 is a RhoGEF that was previously shown to bind to the tight junction protein ZO-1 at perijunctional actomyosin ring (PJAR), a network of cortically organized actin and myosin filaments associated with junctional complexes that regulates cell-cell adhesion and polarization. We show here that ARHGEF11 shows splice isoform expression that differs according to the intrinsic subtype of breast cancer cells and that controls their invasive phenotype. Luminal subtype breast cancer cells express the isoform of ARHGEF11 lacking exon 38 (38-), which binds to ZO-1 at PJAR and is necessary for formation and maintenance of cell-cell junctions. Basal subtype breast cancer cells express the isoform of ARHGEF11 containing exon 38 (38+), which does not bind to ZO-1 and which drives cell migration and motility. Depletion of ARHGEF11 in basal subtype breast cancer cells is sufficient to alter cell morphology from a mesenchymal stellate form with extensive cell protrusions to a cobblestone-like epithelial form, and to suppress growth and survival both in vitro and in vivo. These findings show that the expression of the particular splice isoform of ARHGEF11 is critically linked to the malignant phenotype of breast cancer cells, identifying ARHGEF11 exon 38(+) as a biomarker and target for therapy of breast cancer.