Person: Retamal, Mauricio A.
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Retamal
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Mauricio A.
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Publication Cx40 Levels Regulate Hypoxia-Induced Changes in the Migration, Proliferation, and Formation of Gap Junction Plaques in an Extravillous Trophoblast Cell Model(2024) Rozas Villanueva, María Fernanda; Orellana Villena, Viviana; Alarcón, Rodrigo; Maripillan, Jaime; Martínez, Agustín; Alfaro, Ivan; Retamal, Mauricio A.Background: Extravillous trophoblasts (EVTs) form stratified columns at the placenta–uterus interface. In the closest part to fetal structures, EVTs have a proliferative phenotype, whereas in the closest part to maternal structures, they present a migratory phenotype. During the placentation process, Connexin 40 (Cx40) participates in both the proliferation and migration of EVTs, which occurs under hypoxia. However, a possible interaction between hypoxia and Cx40 has not yet been established. Methods: We developed two cellular models, one with “low Cx40” (Jeg-3), which reflected the expression of this protein found in migratory EVTs, and one with “high Cx40” (Jeg-3/hCx40), which reflected the expression of this protein in proliferative cells. We analyzed the migration and proliferation of these cells under normoxic and hypoxic conditions for 24 h. Jeg-3 cells under hypoxia increased their migratory capacity over their proliferative capacity. However, in Jeg-3/hCx40, the opposite effect was induced. On the other hand, hypoxia promoted gap junction (GJ) plaque formation between neighboring Jeg-3 cells. Similarly, the activation of a nitro oxide (NO)/cGMP/PKG-dependent pathway induced an increase in GJ-plaque formation in Jeg-3 cells. Conclusions: The expression patterns of Cx40 play a crucial role in shaping the responses of EVTs to hypoxia, thereby influencing their migratory or proliferative phenotype. Simultaneously, hypoxia triggers an increase in Cx40 gap junction (GJ) plaque formation through a pathway dependent on NOPublication Connexin46 in the nucleus of cancer cells: a possible role as transcription modulator(2025) Fernández, Ainoa; Orellana, Viviana; Llanquinao, Jesús; Nuñez, Gonzalo; Perez Moreno, Pablo; Contreras, Sebastián; Martin, Alberto; Mammano, Fabio; Alfaro, Ivan; Calderón, Juan; Stehberg, Jimmy; Sáez, Mauricio; Retamal, Mauricio A.Background: Oncogenes drive cancer progression, but few are active exclusively in tumor cells. Connexins (Cxs), traditionally recognized as ion channel proteins, can localize to the nucleus and regulate gene expression, playing key roles in both physiological and pathological processes. Cx46, once thought to be restricted to the eye lens, has been implicated in tumor growth, though its underlying mechanisms remain unclear. This study investigates the nuclear presence of Cx46 in cancer cells and its potential role as a transcriptional modulator. Methods: We employed ChIP-Seq, confocal immunofluorescence, and nuclear protein purification to assess Cx46 localization and DNA interactions. Functional assays were conducted to evaluate its effects on invasion, division, spheroid formation, and mesenchymal marker expression. Single-point mutations and molecular dynamics simulations were used to explore potential Cx46-DNA interactions. Results: Cx46 mRNA upregulation was found in a variety of tumors compared to adjacent healthy tissue. In HeLa cells, which do not express Cx46, its transfection promoted proliferation, invasion and self-renewal capacity, cancer stem cell traits and mesenchymal features. Consistently, in Sk-Mel-2, which naturally express Cx46, reduced Cx46 expression led to a decrease in the similar parameters. In HeLa cells, nuclear Cx46 was detected in two forms, full length 46 kDa and a 30 kDa fragment (GJA3-30 k), ChIP-Seq experiments revealed that Cx46 binds to the DNA at intergenic and promoter regions, leading to the activation of oncogenic pathways. Molecular dynamics simulations suggest that GJA3-30 k dimerizes in a RAD50-like structure, forming stable DNA complexes. Cx46 and in some cases GJA3-30 k were detected in the nuclei of multiple cancer cell lines, including prostate, breast and skin cancers. Conclusions: Our findings reveal a novel nuclear role for Cx46 in cancer, demonstrating its function as a transcriptional regulator and its potential as a therapeutic target.