Institut Curie, Laboratoire d'Oncogénétique, Hôpital René Huguenin, 35 rue Dailly, Saint-Cloud, 92210, France.
J Natl Cancer Inst. 2011 Sep 7;103(17):1323-37. doi: 10.1093/jnci/djr290. Epub 2011 Aug 10.
Fermitin family member 1 (FERMT1, Kindlin-1) is an epithelial-specific regulator of integrin functions and is associated with Kindler syndrome, a genetic disorder characterized by skin blistering, atrophy, and photosensitivity. However, the possible role of kindlin-1 in cancer remains unknown.
Kindlin-1 expression was quantified in several human cancers using quantitative real-time polymerase chain reaction and published microarray datasets. The association between kindlin-1 expression and patient metastasis-free survival (N = 516) was assessed with Kaplan-Meier analyses. Effects of ectopic expression or silencing of kindlin-1 on cell signaling, migration, and invasion were assessed in human breast cancer cell lines using western blotting, immunofluorescence, wound healing assays, and invasion on Matrigel or type I collagen substrates. Breast tumor growth and lung metastasis were evaluated in 12-week-old female BALB/c mice (10 controls and six Kindlin-1-knockdown mice). All statistical tests were two-sided.
Kindlin-1 expression was consistently higher in tumors than in normal tissues in various cancer types metastasizing to the lungs, including colon and bladder cancer. Kindlin-1 expression was associated with metastasis-free survival in both breast and lung adenocarcinoma (breast cancer: hazard ratio of lung metastasis = 2.55, 95% confidence intervals [CI] = 1.39 to 4.69, P = .001; lung cancer: hazard ratio of metastasis = 1.96, 95% CI = 1.25 to 3.07, P = .001). Overexpression of kindlin-1 induced changes indicating epithelial-mesenchymal transition and transforming growth factor beta (TGFβ) signaling, constitutive activation of cell motility, and invasion (number of migrating cells, Kindlin-1 cells vs control, mean = 164.66 vs. 19.00, difference = 145.6, 95% CI = 79.1 to 212.2, P = .004; invasion rate, Kindlin-1-cells vs control = 9.65% vs. 1.92%, difference = 7.73%, 95% CI = 4.75 to 10.70, P < .001). Finally, Kindlin-1 depletion in an orthotopic mouse model statistically significantly inhibited breast tumor growth (P < .001) and lung metastasis (P = .003).
These results suggest a role for kindlin-1 in breast cancer lung metastasis and lung tumorigenesis and advance our understanding of kindlin-1 as a regulator of TGFβ signaling, offering new avenues for therapeutic intervention against cancer progression.
成纤维细胞调节蛋白家族成员 1（FERMT1，Kindlin-1）是整合素功能的上皮特异性调节剂，与 Kindler 综合征有关，Kindler 综合征是一种遗传疾病，其特征为皮肤水疱、萎缩和光敏感。然而，Kindlin-1 在癌症中的可能作用仍不清楚。
使用定量实时聚合酶链反应和已发表的微阵列数据集，对几种人类癌症中的 Kindlin-1 表达进行了定量。使用 Kaplan-Meier 分析评估了 Kindlin-1 表达与 516 例患者无转移生存（无转移生存）之间的关联。使用 Western blot、免疫荧光、划痕愈合试验以及在 Matrigel 或 I 型胶原基质上的侵袭试验，在人乳腺癌细胞系中评估了外源性表达或沉默 Kindlin-1 对细胞信号转导、迁移和侵袭的影响。在 12 周龄雌性 BALB/c 小鼠（10 只对照和 6 只 Kindlin-1 敲低小鼠）中评估了乳腺肿瘤生长和肺转移。所有统计检验均为双侧检验。
在各种转移至肺部的癌症类型中，肿瘤中的 Kindlin-1 表达均明显高于正常组织，包括结肠癌和膀胱癌。Kindlin-1 表达与乳腺癌和肺腺癌的无转移生存相关（乳腺癌：肺转移的危险比=2.55，95%置信区间[CI]为 1.39 至 4.69，P=.001；肺癌：转移的危险比=1.96，95%CI 为 1.25 至 3.07，P=.001）。Kindlin-1 的过表达诱导了上皮-间充质转化和转化生长因子β（TGFβ）信号、细胞迁移和侵袭的组成性激活的变化（迁移细胞数，Kindlin-1 细胞与对照，平均值=164.66 与 19.00，差异=145.6，95%CI 为 79.1 至 212.2，P=.004；侵袭率，Kindlin-1 细胞与对照=9.65%与 1.92%，差异=7.73%，95%CI 为 4.75 至 10.70，P<.001）。最后，在原位小鼠模型中，Kindlin-1 耗竭统计学上显著抑制了乳腺肿瘤生长（P<.001）和肺转移（P=.003）。
这些结果表明 Kindlin-1 在乳腺癌肺转移和肺肿瘤发生中起作用，并增进了我们对 Kindlin-1 作为 TGFβ 信号调节剂的认识，为针对癌症进展的治疗干预提供了新途径。
