Roles of Leptin in Cancer Progression

Kang, Yujin; Moon, Aree

doi:10.4062/biomolther.2010.18.4.363

Cited by 5 publications

(3 citation statements)

References 118 publications

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“…Interestingly, although this protein is mainly secreted by adipocytes, it can also be expressed by pathologically altered cells, such as cancer cells ( 19 , 20 ). Thus, malignant cells can regulate their metabolic activities ( 21 ), promoting uncontrolled cell growth via Wnt/β-catenin ( 22 ), migration, invasion and angiogenesis ( 15 , 23 ), and downregulating apoptosis through a Bcl-2-dependent mechanism ( 21 , 24 ). Accordingly, leptin overexpression is detected in breast cancer cells and neighboring adipocytes, contrasting with normal breast glandular epithelial cells ( 15 , 25 ), promoting the expression of several tissue factors ( 26 ), which suggest an oncogenic role for this adipocytokine ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Serum and Tissue Expression Levels of Leptin and Leptin Receptor Are Putative Markers of Specific Feline Mammary Carcinoma Subtypes

et al. 2021

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Obesity is an established risk factor for breast cancer in post-menopausal women, being associated with elevated serum levels of leptin. Although overweight is a common condition in cat, the role of leptin and its receptor in feline mammary carcinoma remains unsettled. In this study, serum leptin and leptin receptor (ObR) levels were investigated in 58 cats with mammary carcinoma and compared with those of healthy animals, as were the expression levels of leptin and ObR in tumor tissues. The results showed that the Free Leptin Index is significantly decreased in cats with mammary carcinoma (p = 0.0006), particularly in those with luminal B and HER2-positive tumors, and that these animals also present significantly lower serum leptin levels (p < 0.0001 and p < 0.005, respectively). Interestingly, ulcerating tumors (p = 0.0005) and shorter disease-free survival (p = 0.0217) were associated to serum leptin levels above 4.17 pg/mL. In contrast, elevated serum ObR levels were found in all cats with mammary carcinoma (p < 0.0001), with levels above 16.89 ng/mL being associated with smaller tumors (p = 0.0118), estrogen receptor negative status (p = 0.0291) and increased serum levels of CTLA-4 (p = 0.0056), TNF-α (p = 0.0025), PD-1 (p = 0.0023), and PD-L1 (p = 0.0002). In tumor samples, leptin is overexpressed in luminal B and triple-negative carcinomas (p = 0.0046), whereas ObR is found to be overexpressed in luminal B tumors (p = 0.0425). Altogether, our results support the hypothesis that serum levels of leptin and ObR can be used as biomarkers of specific feline mammary carcinoma subtypes, and suggests the use of leptin antagonists as a therapeutic tool, reinforcing the utility of the cat as a cancer model.

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Section: Introductionmentioning

confidence: 99%

Serum and Tissue Expression Levels of Leptin and Leptin Receptor Are Putative Markers of Specific Feline Mammary Carcinoma Subtypes

et al. 2021

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“…These observations prompted us to speculate whether E11 deficiency leads to altered expression of leptin, a pleiotropic adipocytokine that is known to be associated with obesity, adipose tissue inflammation, and cancer ( Myers et al, 2010 ; Abella et al, 2017 ; de Candia et al, 2021 ). In addition to adipocytes, Leptin was found to be expressed in normal epithelial and carcinoma cells and subsequently promotes tumor growth through autocrine and paracrine signaling ( Lin and Hsiao, 2021 ; Kang and Moon, 2010 ). Indeed, we found that the level of leptin transcript was increased by E11 deficiency in the VAT and liver tissues as well as in MEFs ( Figure 6A and Figure 6—figure supplement 1B ).…”

Section: Resultsmentioning

confidence: 99%

Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73γ in tumorigenesis via leptin

Kong,

Yan,

Sun

et al. 2023

eLife

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TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α−η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73α to p73γ isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73α to p73γ isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73γ becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Additionally, we found that E11-deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73γ,necessary for p73γ-mediated oncogenic activity, and associated with p73α to γ isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73γ or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.

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“…These observations prompted us to speculate whether E11 deficiency leads to altered expression of leptin, a pleiotropic adipocytokine that is known to be associated with obesity, adipose tissue inflammation and cancer (65)(66)(67). In addition to adipocytes, Leptin was found to be expressed in normal epithelial and carcinoma cells and subsequently, promotes tumor growth through autocrine and paracrine signaling (68,69). Indeed, we found that the level of leptin transcript was increased by E11 deficiency in the VAT and liver tissues as well as in MEFs (Fig.…”

Section: E11 Deficiency Leads To Elevated Production Of Leptin a Nove...mentioning

confidence: 99%

Isoform-specific Disruption of the TP73 Gene Reveals a Critical Role for TAp73gamma in Tumorigenesis via Leptin

Kong

Yan

Sun

et al. 2022

Preprint

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TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α–η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73α to p73γ isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73α to p73γ isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73γ becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Additionally, we found that E11- deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73γ necessary for p73γ-mediated oncogenic activity, and associated with p73α to γ isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73γ or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.

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Roles of Leptin in Cancer Progression

Cited by 5 publications

References 118 publications

Serum and Tissue Expression Levels of Leptin and Leptin Receptor Are Putative Markers of Specific Feline Mammary Carcinoma Subtypes

Serum and Tissue Expression Levels of Leptin and Leptin Receptor Are Putative Markers of Specific Feline Mammary Carcinoma Subtypes

Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73γ in tumorigenesis via leptin

Isoform-specific Disruption of the TP73 Gene Reveals a Critical Role for TAp73gamma in Tumorigenesis via Leptin

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