Leptin receptor (Ob-R) mRNA expression and serum leptin concentration in patients with colorectal and metastatic colorectal cancer

Erkasap, Nilüfer; Özkurt, Mete; Erkasap, Serdar; Yaşar, Fatih; Uzuner, Kubi̇lay; İhtiyar, Enver; Uslu, Sema; Kara, Mehmet; Bolluk, Özge

doi:10.1590/1414-431x20122559

Cited by 22 publications

(25 citation statements)

References 20 publications

(29 reference statements)

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“…It is noteworthy that a positive correlation was observed among leptin, Ob-R, VEGF, and microvessel density (MVD) in colorectal carcinoma [117]. In accordance with the protein expression (i.e., Ob-R) in tumor tissue that has been discussed above, Erkasap et al documented higher mRNA expression of Ob-R in metastatic growth compared to primary colorectal cancer [119]. …”

Section: Leptin and Tumor Behavior Of The Gastrointestinal Tractmentioning

confidence: 85%

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The potential role of leptin in tumor invasion and metastasis

Ray

Cleary

2017

Cytokine & Growth Factor Reviews

110

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The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin’s association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin’s potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

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Section: Leptin and Tumor Behavior Of The Gastrointestinal Tractmentioning

confidence: 85%

“…Similar to colon cancer [119], metastases from ovarian cancers were found to have higher Ob-Rb expression than what was associated with primary tumors [16]. In vitro studies with various ovarian cancer cell-lines further demonstrated that leptin stimulated cell migration and invasion.…”

Section: Female Reproductive System Cancersmentioning

confidence: 99%

The potential role of leptin in tumor invasion and metastasis

Ray

Cleary

2017

Cytokine & Growth Factor Reviews

110

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“…A positive association has been found between obesity and the risk for the development of various cancers, among them colorectal cancer (CRC) [1, 2]. Several mechanisms have been proposed to explain this association: chronic inflammation, excess production of leptin [3] (concomitantly with an onset of systemic resistance to leptin signaling [4]) and decreased adiponectin secretion in obese subjects, which may deregulate cellular growth and angiogenesis, and therefore promote cancer development and progression [5–8]. …”

Section: Introductionmentioning

confidence: 99%

Leptin and insulin up-regulate miR-4443 to suppress NCOA1 and TRAF4, and decrease the invasiveness of human colon cancer cells

Meerson

Yehuda

2016

BMC Cancer

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BackgroundObesity is a risk factor for colorectal cancer (CRC). Normal and tumor cells respond to metabolic hormones, such as leptin and insulin. Thus, obesity-associated resistance to these hormones likely leads to changes in gene expression and behavior of tumor cells. However, the mechanisms affected by leptin and insulin signaling in CRC cells remain mostly unknown.MethodsWe hypothesized that microRNAs (miRNAs) are involved in the regulation of tumorigenesis-related gene expression in CRC cells by leptin and insulin. To test this hypothesis, miRNA levels in the CRC-derived cell lines HCT-116, HT-29 and DLD-1 were profiled, following leptin and insulin treatment. Candidate miRNAs were validated by RT-qPCR. Predicted miRNA targets with known roles in cancer, were validated by immunoblots and reporter assays in HCT-116 cells. Transfection of HCT-116 cells with candidate miRNA mimic was used to test in vitro effects on proliferation and invasion.ResultsOf ~800 miRNAs profiled, miR-4443 was consistently up-regulated by leptin and insulin in HCT-116 and HT-29, but not in DLD-1, which lacked normal leptin receptor expression. Dose response experiments showed that leptin at 100 ng/ml consistently up-regulated miR-4443 in HCT-116 cells, concomitantly with a significant decrease in cell invasion ability. Transfection with miR-4443 mimic decreased invasion and proliferation of HCT-116 cells. Moreover, leptin and miR-4443 transfection significantly down-regulated endogenous NCOA1 and TRAF4, both predicted targets of miR-4443 with known roles in cancer metastasis. miR-4443 was found to directly regulate TRAF4 and NCOA1, as validated by a reporter assay. The up-regulation of miR-4443 by leptin or insulin was attenuated by the inhibition of MEK1/2.ConclusionsOur findings suggest that miR-4443 acts in a tumor-suppressive manner by down-regulating TRAF4 and NCOA1 downstream of MEK-C/EBP-mediated leptin and insulin signaling, and that insulin and/or leptin resistance (e.g. in obesity) may suppress this pathway and increase the risk of metastatic CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2938-1) contains supplementary material, which is available to authorized users.

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“…A growing body of evidence indicates that the metabolic syndrome (MetS) and expression of various adipokines (leptin and adiponectin) associated with obesity plays a crucial role in the development of colorectal cancer (Hardwick et al, 2001;Hoda et al, 2007;Endo et al, 2011;Aleksandrova et al, 2012;Healy et al, 2012;Erkasap et al, 2013;Gialamas et al, 2013). In obese people, the elevated insulin level, the rapidly growing secretion of leptin, and decreased adiponectin levels altogether activate several signaling pathways that favor carcinogenesis and are associated with colon cancer development.…”

Section: Obesity-leptin and Adiponectinmentioning

confidence: 99%

“…In vitro studies clearly demonstrated that abnormal leptin expression in human colon epithelial cells functions as a growth factor. Leptin or its soluble receptor (ObRb) acts at various stages of neoplastic progression and at stages subsequent to tumor initiation in CRC cell lines (Endo et al, 2011;Erkasap et al, 2013). Moreover, Paik et al (2009) documented that leptin expression increased gradually in the normal-adenoma-adenocarcinoma sequence of CRC development and promoted their proliferation.…”

Section: Obesity-leptin and Adiponectinmentioning

confidence: 99%