BackgroundCancer metastasis is determined by the formation of the metastatic niche and the ability of cancer cells to adapt to microenvironmental stresses. Anoikis resistance is a fundamental feature of metastatic cancer cell survival during metastatic cancer progression. However, the mechanisms underlying anoikis resistance in ovarian cancer are still unclear.MethodsExpressions of miRNA-141 and its downstream targets were evaluated by qPCR, Western blotting, Immunohistochemical (IHC) and in situ hybridization (ISH) assays. The luciferase assays were used to prove KLF12 as the downstream target of miR-141. The cDNA microarray and apoptotic protein arrays were used to identify the targets of miR-141 and KLF12. The competition of KLF12 and Sp1 on survivin promoter was examined by ChIP assay. IHC analysis on ovarian cancer tissue array was used to evaluate the expressions of KLF12 and miR-141 and to show the clinical relevance. The functional studies were performed by in vitro and in vivo tumorigenic assays.ResultsEnforced expression of miR-141 promotes, while knockdown of miR-141 expression inhibits, cell proliferation, anchorage-independent capacity, anoikis resistance, tumor growth and peritoneal metastases of ovarian cancer cells. Bioinformatics and functional analysis identified that Kruppel-related zinc finger protein AP-2rep (KLF12) is directly targeted by miR-141. Consistent with this finding, knockdown of KLF12 phenocopied the effects of miR-141 overexpression in ovarian cancer cells. In contrast, restoration of KLF12 in miR-141-expressing cells significantly attenuated anoikis resistance in ovarian cancer cells via interfering with Sp1-mediated survivin transcription, which inhibits the intrinsic apoptotic pathway and is crucial for ovarian cancer cell survival, anoikis resistance and peritoneal metastases. Immunohistochemical (IHC) and in situ hybridization (ISH) assays confirmed that miRNA-141 expression is inversely correlated with KLF12 expression and significantly associated with advanced ovarian cancers accompanied with distal metastases, underscoring the clinical relevance of our findings.ConclusionsOur data identify a novel signaling axis of miR-141/KLF12/Sp1/survivin in enhancing anoikis resistance and likely serves as a potential therapeutic target for metastatic ovarian cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0582-2) contains supplementary material, which is available to authorized users.

Mitochondria are vital organelles in cells, regulating energy metabolism and apoptosis. Mitochondrial transcellular transfer plays a crucial role during physiological and pathological conditions, such as rescuing recipient cells from bioenergetic deficit and tumorigenesis. Studies have shown several structures that conduct transcellular transfer of mitochondria, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), and Cx43 gap junctions (GJs). The intra- and intercellular transfer of mitochondria is driven by a transport complex. Mitochondrial Rho small GTPase (MIRO) may be the adaptor that connects the transport complex with mitochondria, and myosin XIX is the motor protein of the transport complex, which participates in the transcellular transport of mitochondria through TNTs. In this review, the roles of TNTs, EVs, GJs, and related transport complexes in mitochondrial transcellular transfer are discussed in detail, as well as the formation mechanisms of TNTs and EVs. This review provides the basis for the development of potential clinical therapies targeting the structures of mitochondrial transcellular transfer.

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