Molecular mechanisms underlying obesity associated cancer progression

Department of Biological SciencesWorldwide obese population is continuously increased with being nearly tripled since 1975, and subsequently, increase of metabolic dysfunction has been emerging as a global health care burden that threatens our lives. Numerous studies have reported that the metabolic dysfunctions such as dyslipidemia, hyperglycemia, or hypertension act as risk factor for various disease including cardiovascular disorder, neurological disorders, liver disease, and cancer as well. Especially, breast cancer and hepatocellular carcinoma (HCC) exhibit accelerated pathological development in patients with metabolic syndrome. Although epidemiological data indicated that patients with obesity, or diabetes have elevated cancer incidence and mortality, underlying mechanisms that link epidemiologic associations between metabolic disorder and cancer is poorly understood. In this thesis, we investigated the linking factors involved in association of the metabolic dysfunctions with the CLD and breast cancer, and how they are regulated, and how they contributed to pathophysiology of the diseases. In first part of this study, we addressed the molecular and cellular mechanisms underlying obesity-associated CLD. As a plausible factor that mediates the links between CLD and metabolic stress, we focused on endotrophin, a cleaved product from C5 domain of Collagen6 alpha chain 3 (COL6A3). It is previously documented to be excessively generated in adipose tissues under obese condition, which in turns contributes to pathologic process of the metabolic diseases. Thus, we aimed to investigate the role of endotrophin in CLD and generated transgenic mice model capable of liver-specific endotrophin overexpression, regulated by Dox treatment. Although endotrophin overexpression itself exhibited limited changes in phenotype of liver tissues under normal condition, high expression levels of endotrophin in damaged hepatocytes resulted in JNK mediated hepatic apoptosis and activation of non-parenchymal cells (NPC), leading to further accelerated inflammation, fibrosis, and apoptosis. Furthermore, abrogation of paracrine interactions between hepatocyte and NPC, achieved by endotrophin neutralizing antibodies, led to diminished marker gene expression of inflammation and fibrosis. Finally, in clinical settings, high expression of COL6A3 and endotrophin, its derived peptide, in tumor microenvironment were closely associated with worsened clinical outcomes in HCC patients. Our results shed light on mechanistic insight of endotrophin in CLD progression, by highlighting its role for potential mediator in reciprocal crosstalk between the liver cell populations. Furthermore, inhibitions of endotrophin could be potential therapeutic strategies in CLD patients who are comorbid with obesity or metabolic disorder. Hyperglycemia is associated with increased risk for breast cancers, causing fatal outcomes in the cancer patients. Neuregulin 1 (Nrg1) is overexpressed in breast cancer by hyperglycemia, which is one of the plausible factors that links epidemiologic associations between cancer and diabetes. In second part of the study, we investigated molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression in breast cancer settings. We demonstrate that hyperglycemia leads to active histone modifications at the Nrg1 enhancer, and formation of enhanceosome complexes where RBPJ, P300, and SETD1A are recruited to elevate Nrg1 expression. Deletion of RBPJ-binding sites within the Nrg1 enhancer caused hyperglycemia-driven Nrg1 levels to be diminished, resulting in diminished tumor growth in vitro and in vivo. STZ-induced hyperglycemic mice displayed accelerated tumor growth and lapatinib resistance, whereas lapatinib combined with DAPT administration attenuated the tumor growth under hyperglycemic conditions by dual inhibition of NOTCH and HER2 pathway. Finally, TCGA data analysis revealed that Notch activity was positively correlated with NRG1 levels, and high NRG1 levels predicted worsened clinical outcomes, especially in HER2-amplified breast cancer patients. Our results highlight the hyperglycemia-linked epigenetic regulation of NRG1 as a potential therapeutic target molecule for treating hyperglycemic breast cancer patients. Finally, we aimed to develop anti-cancer drugs for the aggressive breast cancer treatment. A methanolic leaf extract from Pseudolysimachion rotundum var. subintegrum (NC13) and verminoside (Vms), a major constituent of the NC13, were identified as natural product that exhibited chemoadjuvant activity to enhance the anti-cancer effect of cisplatin. The compounds were found to have anti-metastatic activities in combined with cisplatin treatment. The effects of compounds in cisplatin combination treatment were partly mediated through suppression of epithelial???mesenchymal transition (EMT) of the breast cancer cell. Those results imply that the NC13/Vms based chemoadjuvants therapy could be an effective strategy for combination regimens of conventional chemo-drugs. Taken together, we demonstrated the mechanistic insights for understanding impact of metabolic dysfunctions in liver and breast cancer pathology. Furthermore, we suggest that metabolic status of the patients should be importantly considered to achieve optimal therapeutic strategy for the patients with comorbidity.ope

Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer

Breast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial-mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics

Hyperglycemia modulates epigenetic expression of Neuregulin1 through Notch-Rbpj axis

Poor outcomes in diabetic patients are observed across a range of human tumors, suggesting that cancer cells develop unique characteristics under diabetic conditions. Neuregulin1 (NRG1) encodes a ligand for HER3, which is a member of epidermal growth factor family of receptor tyrosine kinases (EGFR). Among the various isoforms of NRG1, NRG1-??1 is overexpressed in the cancer cells by hyperglycemic stimuli via putative distal enhancer activities. However, the specific mechanisms involved in hyperglycemic memory in NRG1 gene is poorly understood. In this study, we investigated how NRG1-??1 is epigenetically regulated under hyperglycemic condition by utilizing enhancer-bait pulldown assay to identify the enhanceosome protein complex. Among the putative candidates, Rbpj was selected as a transcriptional regulator of NRG1-??1, which plays a central role in Notch signaling. Notch signaling was activated in hyperglycemic cancer cells, and DAPT, a notch inhibitor, treatment reduced the Nrg1-??1 expression. We confirmed that Nrg1 enhancer regions which are modulated by hyperglycemia in cancer cells are active motif as enhancer marks such as H3k4me1 and H3k27ac were significantly elevated by hyperglycemia. Our results will provide the fundamental knowledge how diabetes contribute to breast cancer progression, which may be through hyperglycemic memory effects on Nrg1 oncogene

Hyperglycemic memory in metabolism and cancer

Hyperglycemia is a hallmark of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Recent evidence strongly suggests that prolonged exposure to hyperglycemia can epigenetically modify gene expression profiles in human cells and that this effect is sustained even after hyperglycemic control is therapeutically achieved; this phenomenon is called hyperglycemic memory. This metabolic memory effect contributes substantially to the pathology of various diabetic complications, such as diabetic retinopathy, hypertension, and diabetic nephropathy. Due to the metabolic memory in cells, diabetic patients suffer from various complications, even after hyperglycemia is controlled. With regard to this strong association between diabetes and cancer risk, cancer cells have emerged as key target cells of hyperglycemic memory in diabetic cancer patients. In this review, we will discuss the recent understandings of the molecular mechanisms underlying hyperglycemic memory in metabolism and cancer.clos

Extracellular matrix remodeling facilitates obesity-associated cancer progression

Obesity, a global public health concern, is an important risk factor for metabolic diseases and several cancers. Fibro-inflammation in adipose tissues (ATs) is tightly associated with the pathologies of obesity; excessive or uncontrolled extracellular matrix (ECM) production in AT has a crucial role in this pathogenesis. The ECM is a critical and functional component of various tissues, providing a mechanical and chemical network of proteins that controls cell survival, development, and tissue repair. The ECM is tightly regulated and dynamically remodeled; this is an important factor for AT expansion and can result in modifications to the physical shape and biological function of AT. Here, we focus on ECM remodeling in AT and how it affects obesity-related cancer progression

Role of endotrophin in chronic liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cirrhosis, liver cancer, hypertension, and atherosclerosis. Fibrotic liver is characterized by pathological accumulation of Extracullar matrix (ECM) proteins. Type VI collagen alpha3 chain (Col6a3) is one of biomarker for hepatic fibrosis and its cleaved form, endotropohin (ETP), plays critical roles in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of Col6a3-derived peptides ETP, on chronic liver disease progression such as NASH and liver cancer. By utilizing a doxycycline (Dox)-inducible liver-specific ETP overexpressing mouse model under the NAFLD model (SREBP1a transgenic) background, we investigated the role of ETP on hepatic inflammation, fibrosis and insulin resistance. The accumulation of ETP induces hepatic inflammation, and fibrosis development with insulin resistance. Surprisingly, ETP overexpression can induce liver cancer after treatment of Dox for 10 months. Our data reveal that ETP can act as a ???second hit??? on NAFLD condition and induce progression of NASH. We provide new evidences for understanding the relationship between ETP and chronic liver disease