FAM3B/PANDER, é uma nova proteína tipo citocina pertencente a família FAM3. Foram reveladas algumas similaridades estruturais entre o FAM3B e outras citocinas associadas ao câncer, como IL-6 e FAM3C suportando a hipótese, de que FAM3B também poderia estar envolvido na progressão tumoral. Considerando que o FAM3B é expresso por tumores de mama, este trabalho dedicou-se a elucidar suas possíveis funções em tumores, a partir de um modelo de superexpressão na linhagem celular tumoral da mama, MDA-MB-231. Ensaios celulares e moleculares sugeriram que o FAM3B é capaz de conferir, proteção à morte celular e de aumentar taxa de migração nas células MDA-MB-231 via, principalmente, Bcl-2 e Bcl-xL. Em concordância, os resultados in vivo demonstraram aumento do volume e peso tumoral, com aumento da expressão de Bcl-2 nos tumores dos animais inoculados com as células MDA-MB-231-FAM3B. Estes resultados indicam que esta proteína, exerce funções nas etapas de invasão e metástase em tumores de mama, o que permite considerar o FAM3B, como um possível candidato a marcador tumoral. / FAM3B/PANDER is a new cytokine-like protein, member of the new FAM3 family. Recent data has been shown similarities between FAM3B/PANDER and others citokines involved in tumor progression, like IL-6 and FAM3C/ILEI, supporting the hypothesis that FAM3B is also involved in tumor progression. In Silico data revealed that FAM3B is expressed by breast tumors and using the overexpression of FAM3B in MDA-MB-231 tumor cell line, the aim was evaluated possible roles of FAM3B in breast tumor progression. The results revealed that FAM3B overexpression inhibits cell death and promotes cell migration in MDA-MB-231 cell line, through, at least in parts, Bcl-2 and Bcl-xL pathways. In agreement, in vivo results shown an increase in volume, weight tumors and increase expression of Bcl-2 in mice with cells overexpressing FAM3B.These results suggest important functions of this protein in cell invasiveness and migration, which allows us to consider, FAM3B as a possible future candidate as a molecular biomarker.

PANDER/FAM3B (PANcreatic-DERived factor) é uma citocina capaz de induzir apoptose em células-β secretoras de insulina e regular a homeostase da glicose nos tecidos periféricos. Considerando que PANDER/FAM3B também é expresso em tumores de próstata, o presente trabalho avaliou o papel desta citocina na inibição da apoptose in vitro, assim como o crescimento e invasividade tumoral de células de carcinoma de próstata da linhagem DU145 in vivo, usando o modelo de superexpressão estável mediada por lentivirus. Os nossos resultados apontam um aumento da viabilidade e uma diminuição da morte celular em células que superexpressam PANDER quando comparadas ao grupo controle. Este efeito protetor é acompanhado por um aumento da expressão de genes anti-apoptoticos e uma diminuição da atividade proteolítica das caspases. Por outro lado, a superexpressão de PANDER/FAM3B por tumores in vivo se correlaciona com aumento da massa tumoral e o aumento de vasos sanguíneos nos tumores. Em síntese, nossos dados demonstram que, em contraste ao papel observado em células β-pancreáticas, o PANDER/FAM3B inibe morte celular e promove a tumorigenicidade e o crescimento tumoral in vivo, sugerindo ao mesmo tempo, algum envolvimento com angiogênese e metástase em células DU145. / PANDER / FAM3B (pancreatic-derived factor) is a cytokine capable of inducing apoptosis in secreting β-cells and insulin to regulate glucose homeostasis in peripheral tissues. Whereas PANDER / FAM3B is also expressed in prostate tumors, this study evaluated the role of this cytokine in the inhibition of apoptosis in vitro as well as tumor growth and invasiveness of prostate carcinoma DU145 cells lineage in vivo, using the model Stable overexpression mediated by lentivirus. Our results suggest that increased viability and decreased cell death in cells that overexpress PANDER when compared to the control group. This protective effect is accompanied by an increased expression of anti-apoptotic genes and a decrease in proteolytic activity of caspases. Moreover, overexpression of PANDER / FAM3B by tumors in vivo correlates with increased tumor mass and the increase of blood vessels in tumors. In summary, our data demonstrate that in contrast to the role observed in pancreatic cells, PANDER / FAM3B inhibits cell death and promotes tumorigenicity and tumor growth in vivo, suggesting at the same time, some involvement in angiogenesis and metastasis in cell DU145.

PANDER/FAM3B (PANcreatic-DERived factor) é uma citocina capaz de induzir apoptose em células-β secretoras de insulina e regular a homeostase da glicose nos tecidos periféricos. Considerando que PANDER/FAM3B também é expresso em tumores de próstata, o presente trabalho avaliou o papel desta citocina na inibição da apoptose in vitro, assim como o crescimento e invasividade tumoral de células de carcinoma de próstata da linhagem DU145 in vivo, usando o modelo de superexpressão estável mediada por lentivirus. Os nossos resultados apontam um aumento da viabilidade e uma diminuição da morte celular em células que superexpressam PANDER quando comparadas ao grupo controle. Este efeito protetor é acompanhado por um aumento da expressão de genes anti-apoptoticos e uma diminuição da atividade proteolítica das caspases. Por outro lado, a superexpressão de PANDER/FAM3B por tumores in vivo se correlaciona com aumento da massa tumoral e o aumento de vasos sanguíneos nos tumores. Em síntese, nossos dados demonstram que, em contraste ao papel observado em células β-pancreáticas, o PANDER/FAM3B inibe morte celular e promove a tumorigenicidade e o crescimento tumoral in vivo, sugerindo ao mesmo tempo, algum envolvimento com angiogênese e metástase em células DU145. / PANDER / FAM3B (pancreatic-derived factor) is a cytokine capable of inducing apoptosis in secreting β-cells and insulin to regulate glucose homeostasis in peripheral tissues. Whereas PANDER / FAM3B is also expressed in prostate tumors, this study evaluated the role of this cytokine in the inhibition of apoptosis in vitro as well as tumor growth and invasiveness of prostate carcinoma DU145 cells lineage in vivo, using the model Stable overexpression mediated by lentivirus. Our results suggest that increased viability and decreased cell death in cells that overexpress PANDER when compared to the control group. This protective effect is accompanied by an increased expression of anti-apoptotic genes and a decrease in proteolytic activity of caspases. Moreover, overexpression of PANDER / FAM3B by tumors in vivo correlates with increased tumor mass and the increase of blood vessels in tumors. In summary, our data demonstrate that in contrast to the role observed in pancreatic cells, PANDER / FAM3B inhibits cell death and promotes tumorigenicity and tumor growth in vivo, suggesting at the same time, some involvement in angiogenesis and metastasis in cell DU145.

FAM3B/PANDER, é uma nova proteína tipo citocina pertencente a família FAM3. Foram reveladas algumas similaridades estruturais entre o FAM3B e outras citocinas associadas ao câncer, como IL-6 e FAM3C suportando a hipótese, de que FAM3B também poderia estar envolvido na progressão tumoral. Considerando que o FAM3B é expresso por tumores de mama, este trabalho dedicou-se a elucidar suas possíveis funções em tumores, a partir de um modelo de superexpressão na linhagem celular tumoral da mama, MDA-MB-231. Ensaios celulares e moleculares sugeriram que o FAM3B é capaz de conferir, proteção à morte celular e de aumentar taxa de migração nas células MDA-MB-231 via, principalmente, Bcl-2 e Bcl-xL. Em concordância, os resultados in vivo demonstraram aumento do volume e peso tumoral, com aumento da expressão de Bcl-2 nos tumores dos animais inoculados com as células MDA-MB-231-FAM3B. Estes resultados indicam que esta proteína, exerce funções nas etapas de invasão e metástase em tumores de mama, o que permite considerar o FAM3B, como um possível candidato a marcador tumoral. / FAM3B/PANDER is a new cytokine-like protein, member of the new FAM3 family. Recent data has been shown similarities between FAM3B/PANDER and others citokines involved in tumor progression, like IL-6 and FAM3C/ILEI, supporting the hypothesis that FAM3B is also involved in tumor progression. In Silico data revealed that FAM3B is expressed by breast tumors and using the overexpression of FAM3B in MDA-MB-231 tumor cell line, the aim was evaluated possible roles of FAM3B in breast tumor progression. The results revealed that FAM3B overexpression inhibits cell death and promotes cell migration in MDA-MB-231 cell line, through, at least in parts, Bcl-2 and Bcl-xL pathways. In agreement, in vivo results shown an increase in volume, weight tumors and increase expression of Bcl-2 in mice with cells overexpressing FAM3B.These results suggest important functions of this protein in cell invasiveness and migration, which allows us to consider, FAM3B as a possible future candidate as a molecular biomarker.

PANcreatic-DERived factor (PANDER, FAM3B) has been shown to regulate glycemic levels via interactions with both pancreatic islets and the liver. Although PANDER is predominantly expressed from the endocrine pancreas, recent work has provided sufficient evidence that the liver may also be an additional tissue source of PANDER production. At physiological levels, PANDER is capable of disrupting insulin signaling and promoting increased hepatic glucose production. As shown in some animal models, strong expression of PANDER, induced by viral delivery within the liver, induces hepatic steatosis. However, no studies to date have explicitly characterized the transcriptional regulation of PANDER from the liver. Therefore, our investigation elucidated the nutrient and hormonal regulation of the hepatic PANDER promoter. Initial RNA-ligated rapid amplification of cDNA ends identified a novel transcription start site (TSS) approximately 26 bp upstream of the PANDER translational start codon not previously revealed in pancreatic β-cell lines. Western evaluation of various murine tissues demonstrated robust expression in the liver and brain. Promoter analysis identified strong tissue-specific activity of the PANDER promoter in both human and murine liver-derived cell lines. The minimal element responsible for maximal promoter activity within hepatic cell lines was located between -293 to -3 of the identified TSS. PANDER promoter activity was inhibited by both insulin and palmitate, whereas glucose strongly increased expression. The minimal element was responsible for maximal glucose-responsive and basal activity. Co-transfection reporter assays, chromatin-immunoprecipitation (ChIP) and site-directed mutagenesis revealed that the carbohydrate-responsive element binding protein (ChREBP) increased PANDER promoter activity and interacted with the PANDER promoter. E-box 3 was shown to be critical for basal and glucose responsive expression. In summary, in-vitro and in-vivo glucose is a potent stimulator of the PANDER promoter within the liver and this response may be facilitated by ChREBP.

PANcreatic-DERived Factor (PANDER), or FAM3B, is a 235-amino acid protein strongly expressed within and secreted from the endocrine pancreas. Research surrounding PANDER has revealed a large role for the protein in maintaining glucose homeostasis, as evidenced by several Ad-PANDER overexpressing murine models, our lab's pancreas-specific PANDER transgenic overexpressor, and most recently our mixed genetic C57/129J PANDER knockout (PANKO) mouse. However, PANDER's overall role in glycemic regulation and glucose homeostasis has yet to be studied in a purebred C57BL/6J PANDER knockout model. Here we present the first phenotypic characterization of our global PANDER knockout mouse on a C57BL/6J background (PANKO-C57) where we examined metabolics through glucose/insulin tolerance testing, fasting glycemia, and body weights, the concentrations of hormonal analytes along with lipids and corticosterones, and full elucidation of hepatic insulin signaling through the insulin signaling cascade. Overall, the PANKO-C57 mice exhibited increased body weights with enhanced glucose tolerance and lower fasting glycemia, similar peripheral insulin sensitivities, increased hepatic lipidemia, and enhanced hepatic insulin signaling at critical insulin signaling molecules. Taken together, the PANKO-C57 demonstrates that the disruption of PANDER results in selectively enhanced hepatic insulin signaling yet with increased lipidemia and overall body weight. These findings reveal a novel role for PANDER in differentially controlling lipogenesis and hepatic glucose production that may selectively impact overall glycemic control and potentially facilitate the onset and/or progression of type 2 diabetes.