The poor prognosis of esophageal carcinoma (ESCA) highlights the need to identify novel targets for ESCA treatment. We found that inhibitor of differentiation 4 (ID4) was decreased in ESCA tumor tissues and its expression was associated with the survival of ESCA patients. However, the role of ID4 in ESCA remains unclear. Here, in this study, we found that overexpression of ID4 suppressed the cell proliferation of ESCA in vitro as well as tumor growth in vivo, whereas knockdown of ID4 presented the opposite trend. On the other hand, ESCA cells with overexpression of ID4 reduced macrophage migration and M2 polarization. However, significant increases in macrophage migration and M2 polarization were observed in cultures with ID4 silence. Interestingly, CCL2 was found to mediate the function of ID4 on macrophage polarization. Mechanistically, we identified for the first time that ID4 interacted physically with TCF4 to inactivate TCF4 transcriptional activity, which led to a decrease in CCL2 expression. Moreover, RNA binding protein cell cycle associated protein 1 (CAPRIN1) bound to ID4 mRNA and downregulated its stability, which may contribute to its low expression in ESCA. Taken together, these results support a novel hypothesis that ID4 downregulation may contribute to the development of ESCA by interacting with TCF4, resulting in abnormal proliferation of ESCA cells and tumor-associated macrophage infiltration. ID4 may contribute to the innovation of ESCA biotherapy.
Implications: ID4 inhibits ESCA through suppresses cancer cell proliferation and macrophage M2 polarization, and ID4 could be a potential prognostic marker for patients with ESCA.
Hairui Tian,Xingju Wang,Xiaoxiao Li,Weixiang Song,Jiaqi Mi,Kang Zou
In the orchestrated environment of the testicular niche, the equilibrium between self-renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously maintained, ensuring a stable stem cell reserve and robust spermatogenesis. Within this milieu, extracellular vesicles, specifically exosomes, have emerged as critical conveyors of intercellular communication. Despite their recognized significance, the implications of testicular exosomes in modulating SSC fate remain incompletely characterized. Given the fundamental support and regulatory influence of Sertoli cells (SCs) on SSCs, we were compelled to explore the role of SC-derived exosomes (SC-EXOs) in the SSC-testicular niche. Our investigation hinged on the hypothesis that SC-EXOs, secreted by SCs from the testes of 5-day-old mice—a developmental juncture marking the onset of SSC differentiation—participate in the regulation of this process. We discovered that exposure to SC-EXOs resulted in an upsurge of PLZF, MVH, and STRA8 expression in SSC cultures, concomitant with a diminution of ID4 and GFRA1 levels. Intriguingly, obstructing exosomal communication in a SC-SSC coculture system with the exosome inhibitor GW4869 attenuated SSC differentiation, suggesting that SC-EXOs may modulate this process via paracrine signaling. Further scrutiny revealed the presence of miR-493-5p within SC-EXOs, which suppresses Gdnf mRNA in SCs to indirectly restrain SSC differentiation through the modulation of GDNF expression—an indication of autocrine regulation. Collectively, our findings illuminate the complex regulatory schema by which SC-EXOs affect SSC differentiation, offering novel perspectives and laying the groundwork for future preclinical and clinical investigations.
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