Osteosarcoma (OS) is a rare malignant bone tumor but is one leading cause of cancer mortality in childhood and adolescence. Cancer metastasis accounts for the primary reason for treatment failure in OS patients. The dynamic organization of the cytoskeleton is fundamental for cell motility, migration, and cancer metastasis. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is an oncogene participating in various biological progress central to cancer biogenesis. However, the potential roles of LAPTM4B in OS and the related mechanisms remain unknown. Here, we established the elevated LAPTM4B expression in OS, and it is essential in regulating stress fiber organization through RhoA–LIMK–cofilin signaling pathway. In terms of mechanism, our data revealed that LAPTM4B promotes RhoA protein stability by suppressing the ubiquitin-mediated proteasome degradation pathway. Moreover, our data show that miR-137, rather than gene copy number and methylation status, contributes to the upregulation of LAPTM4B in OS. We report that miR-137 is capable of regulating stress fiber arrangement, OS cell migration, and metastasis via targeting LAPTM4B. Combining results from cells, patients’ tissue samples, the animal model, and cancer databases, this study further suggests that the miR-137–LAPTM4B axis represents a clinically relevant pathway in OS progression and a viable target for novel therapeutics.

骨肉瘤 (OS) 是一种罕见的恶性骨肿瘤，但却是儿童和青少年癌症死亡的主要原因之一。癌症转移是 OS 患者治疗失败的主要原因。细胞骨架的动态组织是细胞运动、迁移和癌症转移的基础。溶酶体相关蛋白跨膜 4B (LAPTM4B) 是一种致癌基因，参与对癌症生物发生至关重要的各种生物学进程。然而，LAPTM4B 在 OS 中的潜在作用和相关机制仍然未知。在这里，我们确定了 OS 中升高的 LAPTM4B 表达，它对于通过 RhoA–LIMK–cofilin 信号通路调节应力纤维组织至关重要。在机制方面，我们的数据显示 LAPTM4B 通过抑制泛素介导的蛋白酶体降解途径来促进 RhoA 蛋白的稳定性。此外，我们的数据显示 miR-137，而不是基因拷贝数和甲基化状态，有助于 OS 中 LAPTM4B 的上调。我们报告说，miR-137 能够通过靶向 LAPTM4B 来调节应力纤维排列、OS 细胞迁移和转移。结合来自细胞、患者组织样本、动物模型和癌症数据库的结果，这项研究进一步表明，miR-137–LAPTM4B 轴代表了 OS 进展中的临床相关途径和新疗法的可行靶点。我们报告说，miR-137 能够通过靶向 LAPTM4B 来调节应力纤维排列、OS 细胞迁移和转移。结合来自细胞、患者组织样本、动物模型和癌症数据库的结果，这项研究进一步表明，miR-137–LAPTM4B 轴代表了 OS 进展中的临床相关途径和新疗法的可行靶点。我们报告说，miR-137 能够通过靶向 LAPTM4B 来调节应力纤维排列、OS 细胞迁移和转移。结合来自细胞、患者组织样本、动物模型和癌症数据库的结果，这项研究进一步表明，miR-137–LAPTM4B 轴代表了 OS 进展中的临床相关途径和新疗法的可行靶点。