No abstract

No abstract

Metastasis is the main cause of death in patients with cancer, and understanding the mechanisms of metastatic processes is essential for the development of cancer therapy. Although the role of several cell adhesion, migration or proliferation molecules in metastasis is established, a novel target for cancer therapy remains to be discovered. Previously, we reported that fad104 (factor for adipocyte differentiation 104), a regulatory factor of adipogenesis, regulates cell adhesion and migration. In this report, we clarify the role of fad104 in the invasion and metastasis of cancer cells. The expression level of fad104 in highly metastatic melanoma A375SM cells was lower than that in poorly metastatic melanoma A375C6 cells. Reduction of fad104 expression enhanced the migration and invasion of melanoma cells, while over-expression of FAD104 inhibited migration and invasion. In addition, melanoma cells stably expressing FAD104 showed a reduction in formation of lung colonization compared with control cells. FAD104 interacted with STAT3 and down-regulated the phosphorylation level of STAT3 in melanoma cells. These findings together demonstrate that fad104 suppressed the invasion and metastasis of melanoma cells by inhibiting activation of the STAT3 signaling pathway. These findings will aid a comprehensive description of the mechanism that controls the invasion and metastasis of cancer cells.

Osteogenesis is a complex process that is orchestrated by several growth factors, extracellular cues, signaling molecules, and transcriptional factors. Understanding the mechanisms of bone formation is pivotal for clarifying the pathogenesis of bone diseases. Previously, we reported that fad104 (factor for adipocyte differentiation 104), a novel positive regulator of adipocyte differentiation, negatively regulated the differentiation of mouse embryonic fibroblasts into osteocytes. However, the physiological role of fad104 in bone formation has not been elucidated. Here, we clarified the role of fad104 in bone formation in vivo and in vitro. fad104 disruption caused craniosynostosis-like premature ossification of the calvarial bone. Furthermore, analyses using primary calvarial cells revealed that fad104 negatively regulated differentiation and BMP/Smad signaling pathway. FAD104 interacted with Smad1/5/8. The N-terminal region of FAD104, which contains a proline-rich motif, was capable of binding to Smad1/5/8. We demonstrated that down-regulation of Smad1/5/8 phosphorylation by FAD104 is dependent on the N-terminal region of FAD104 and that fad104 functions as a novel negative regulator of BMP/Smad signaling and is required for proper development for calvarial bone. These findings will aid a comprehensive description of the mechanism that controls normal and premature calvarial ossification.

Anchorage-independent growth is one of the defining characteristics of cancer cells. Many oncogenes and tumor suppressor genes are involved in regulating this type of growth. Factor for adipocyte differentiation 104 gene ( fad104) is a regulator of adipogenesis and osteogenesis. Previously, we reported that fad104 suppressed metastasis as well as invasion of melanoma cells. However, it is unclear whether fad104 is involved in malignant transformation, which is associated with metastasis. In this study, we revealed that fad104 negatively regulated the colony forming activity of melanoma cells. The presence of the N-terminal region of FAD104 was required for the regulation of malignant transformation of melanoma cells. In addition, the deletion mutant of FAD104 that contained the N-terminal region and transmembrane domain interacted with signal transducer and activator of transcription 3 (STAT3) and suppressed STAT3 activity. However, the deletion mutant of FAD104 lacking the N-terminal region did not influence the interaction with STAT3 or suppress the STAT3 activity. Moreover, FAD104 interacted with the C-terminal region of STAT3. In summary, we demonstrated that fad104 suppressed anchorage-independent growth of melanoma cells, and that the N-terminal region of FAD104 is essential for inhibiting malignant transformation and STAT3 activity.Key words anchorage-independent growth; malignant transformation; melanoma; factor for adipocyte differentiation 104 (FAD104); signal transducer and activator of transcription 3 (STAT3) Melanoma is one of the most frequently occurring malignant tumors and is characterized by its high rate of invasion and metastasis. The development of metastatic diseases is highly complex. Anchorage-independent growth is a crucial step in the acquisition of metastatic potential.1) Tumor cells that have a high potential for anchorage-independent growth possess the ability to migrate through the body, colonize other tissues, and grow metastatically.2) Therefore, understanding the mechanisms by which anchorage-independent cancer cell growth is regulated is essential for the development of therapies for metastatic cancer. Although multiple genetic factors for anchorage-independent growth have been identified, little is known about the molecular basis for the capacity for anchorage-independent growth. 3,4) Previously, using the polymerase chain reaction (PCR) subtraction method, we identified unknown genes, whose expressions were elevated at the early period in adipogenesis, such as factor for adipocyte differentiation 24 gene ( fad24), fad49, fad104, and fad158, and showed that they promoted adipocyte differentiation in mouse 3T3-L1 cells.5-10) The expression of fad104, also known as fndc3b, is transiently increased 3 h after adipogenic induction. FAD104 has a proline-rich region, nine fibronectin type III domains, and a transmembrane region. Our previous study revealed that fad104 functioned as positive and negative regulator for adipogenesis and osteoblast differentiation, respectively. 11) Furth...