B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and cancer progression in many types of cancers, mechanistic studies on how B7-H3 regulates cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast cancer stem cell population and promotes cancer development. Depletion of B7-H3 in breast cancer significantly inhibits the cancer stem cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases stem cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced stem cells. This study reports novel functions of B7-H3 in regulating breast cancer stem cell enrichment. The novel mechanism for B7-H3-induced stem cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming cancer cell resistance to chemotherapy.

中文翻译：

---

免疫调节蛋白B7-H3通过MVP介导的MEK激活来调节癌症干细胞的富集和耐药性。

B7-H3是一种促进肿瘤的糖蛋白，在大多数正常组织中低水平表达，但在各种人类癌症中过表达，这与疾病进展和患者预后不良有关。尽管许多出版物已经报道了B7-H3与许多类型的癌症中癌症进展之间的相关性，但有关B7-H3如何调节癌症恶性的机制研究很少，并且几乎不知道B7-H3在耐药中的作用机理。在这里我们报告了一个新发现，即B7-H3的上调增加了乳腺癌干细胞的数量并促进了癌症的发展。乳腺癌中B7-H3的消耗显着抑制了癌干细胞。通过免疫沉淀和质谱分析，我们发现B7-H3与主要穹顶蛋白（MVP）相关，并通过增强MVP的B-RAF和MEK相互作用激活MEK。B7-H3表达通过与MVP结合而增加，从而调节MAPK激酶途径的激活，从而增加干细胞的数量。MVP的耗竭阻止了B7-H3诱导的MEK激活，并显着抑制了B7-H3诱导的干细胞。这项研究报告了B7-H3在调节乳腺癌干细胞富集中的新功能。通过独立于经典Ras途径调节MVP / MEK信号轴，B7-H3诱导的干细胞增殖的新机制可能对克服癌细胞对化学疗法的抵抗力的策略具有重要意义。B7-H3表达通过与MVP结合而增加，从而调节MAPK激酶途径的激活，从而增加干细胞的数量。MVP的耗竭阻止了B7-H3诱导的MEK激活，并显着抑制了B7-H3诱导的干细胞。这项研究报告了B7-H3在调节乳腺癌干细胞富集中的新功能。通过独立于经典Ras途径调节MVP / MEK信号轴，B7-H3诱导的干细胞增殖的新机制可能对克服癌细胞对化学疗法的抵抗力的策略具有重要意义。B7-H3表达通过与MVP结合而增加，从而调节MAPK激酶途径的激活，从而增加干细胞的数量。MVP的耗竭阻止了B7-H3诱导的MEK激活，并显着抑制了B7-H3诱导的干细胞。这项研究报告了B7-H3在调节乳腺癌干细胞富集中的新功能。通过独立于经典Ras途径调节MVP / MEK信号轴，B7-H3诱导的干细胞增殖的新机制可能对克服癌细胞对化学疗法的抵抗力的策略具有重要意义。