Cholesterol promotes the migration and invasion of renal carcinoma cells by regulating the KLF5/miR-27a/FBXW7 pathway

Zheng, Lianwen; Liu, Xiaowen; Liu, Shuai; Cao, Qi

doi:10.1016/j.bbrc.2018.05.122

Cited by 46 publications

(41 citation statements)

References 26 publications

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“…Few studies also confirmed the role of cholesterol/intracellular lipids in cancer progression and metastasis [14, 43]. We had also used cholesterol depleting MBCD to see cancer promoting role of cholesterol.…”

Section: Discussionmentioning

confidence: 95%

“…Many studies also demonstrated a cancer promoting role of sterol regulatory element-binding protein 1 (SREBP1)] which promotes transcription of both HMGCoR and LDLR genes [12, 13]. Recent study documented that cholesterol increased cancer cell migration and invasion in renal carcinoma [14]. Thus, the current research work was mainly focused to examine the effect of metformin on cholesterol content in breast cancer cells, since no studies have yet been conducted to see the influence of metformin treatment on cellular cholesterol level in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells

et al. 2019

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Metformin, a widely prescribed anti-diabetic drug, shows anticancer activity in various cancer types. Few studies documented that there was a decreased level of LDL and total cholesterol in blood serum of metformin users. Based on these views, this study aimed to determine if metformin exhibits anticancer activity by alleviating cholesterol level in cancer cells. The present study found that treatment of breast cancer MDA-MB-231 cells with metformin significantly decreased cholesterol content with concomitant inhibition of various cholesterol regulatory genes (e.g., HMGCoR, LDLR and SREBP1). Metformin decreased cell viability, migration and stemness in metastatic MDA-MB-231 cells. Similarly, metformin treatment suppressed expressions of anti-apoptotic genes BCL2 and Bcl-xL, and mesenchymal genes vimentin, N-cadherin, Zeb1 and Zeb2 with simultaneous enhancement of apoptotic caspase 3 and Bax, and epithelial genes E-cadherin and keratin 19 expressions, confirming an inhibitory effect of metformin in tumorigenesis. Similar to metformin, depletion of cholesterol by methyl beta cyclodextrin (MBCD) diminished cell viability, migration, EMT and stemness in breast cancer cells. Moreover, metformin-inhibited cell viability, migration, colony and sphere formations were reversed back by cholesterol treatment. Similarly, cholesterol treatment inverted metformin-reduced several gene expressions (e.g., Bcl-xL, BCL2, Zeb1, vimentin, and BMI-1). Additionally, zymography data demonstrated that cholesterol upregulated metformin-suppressed MMP activity. These findings suggested that metformin revealed anticancer activity by lowering of cholesterol content in breast cancer cells. Thus, this study, for the first time, unravelled this additional mechanism of metformin-mediated anticancer activity.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells

et al. 2019

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“…The ccRCC cells have the aggregation characteristics of cholesterol, cholesterol ester, and other lipids (20), suggesting that the content of cholesterol and cholesterol ester in ccRCC tissues is higher than that in normal kidney tissue (21). Cholesterol has been demonstrated to slightly promote the ccRCC cell proliferation, but it significantly increases the capacities of invasion and migration by regulating the KLF5/miR-27a/FBXW7 axis (22). APOC1 is present in chylomicrons, VLDL, and HDL.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein C1 (APOC1): A Novel Diagnostic and Prognostic Biomarker for Clear Cell Renal Cell Carcinoma

et al. 2020

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Background: Apolipoprotein C1 (APOC1) has been proved to play a critical role in gastric, breast, lung, and pancreatic cancer. However, the relationship between APOC1 and urinary tumors remains unclear. This study aimed to assess the diagnostic and prognostic value of APOC1 in urinary tumors. Methods: We performed a pan analysis of APOC1 mRNA expression in urinary cancer using the Gene Expression Profiling Interactive Analysis (GEPIA) database. To further investigate the prognostic value of APOC1 expression in urinary cancers, the Kaplan-Meier plotter database was used. Furthermore, we collected the tumor and adjacent normal samples of 32 ccRCC patients to perform qRT-PCR and western blotting assays. A total of 72 cases with ccRCC were analyzed using tissue microarrays (TMAs). Results: Our results based on Kaplan-Meier plotter database indicated that a high expression of APOC1 may lead to poor overall survival (OS, p = 0.0019) in patients with ccRCC. Furthermore, the cancer stages and tumor grade of ccRCC appeared to be strongly linked with APOC1 expression according to UALCAN database. Hence, we reached a preliminary conclusion that APOC1 may play a key role in the tumorigenesis and progression of ccRCC. Furthermore, the Kaplan-Meier survival curve analyses of 72 clinical patients indicated that high expression of APOC1 was associated with poor progression-free survival (PFS, p = 0.007) and OS (p = 0.022). In addition, univariate Cox regression analysis confirmed the significant relationship between APOC1 expression and survival (p = 0.038). The TMAs analysis in combination with the patients' clinicopathological features was also performed. The expression of APOC1 was found to be significantly correlated with the tumor size (p = 0.018) and histological grade (p = 0.016). Conclusions: In conclusion, the findings of our study suggest that APOC1 may serve as a novel diagnostic and prognostic biomarker for ccRCC. Further evidence on the mechanism of APOC1 promoting tumor progression may transform it to a new therapeutic target for the treatment of ccRCC.

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“…HIF-1α stable long non-coding RNA (HISLA) in exosomes derived from cancer-associated macrophages stabilizes HIF-1α via proline hydroxylase domain 2 (PHD2) and HIF-1α [98]. It seems that high lipid content is more conducive for normal cells to absorb cancer-derived exosomes [99,100], and induce normal cells to transform into cancer cells [81,101]. At present, disorder of lipid metabolism mediated by exosomes is increasingly recognized as a characteristic of cancer cells and may be a factor in the malignant cancer progression and metastatic behavior [102].…”

Section: Cancermentioning

confidence: 99%

“…Mechanically, disorder of lipid metabolism also facilitates cancer invasion and metastasis by up-regulating oncogenes, such as c-Myb, c-Myc, c-Jun, cyclin-E, Notch and mTOR [100]. Roberg-Larsen et al also confirmed that compared to exosomes derived from an estrogen receptor (ER-) breast cancer cell line (MDA-MB-231), the levels of 27-OHC in exosomes from an ER + breast cancer cell line (MCF-7) has increased, which provides complementary information with diagnostic value [108].…”

Section: Cancermentioning

confidence: 99%

The crosstalk: exosomes and lipid metabolism

et al. 2020

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Exosomes have been considered as novel and potent vehicles of intercellular communication, instead of "cell dust". Exosomes are consistent with anucleate cells, and organelles with lipid bilayer consisting of the proteins and abundant lipid, enhancing their "rigidity" and "flexibility". Neighboring cells or distant cells are capable of exchanging genetic or metabolic information via exosomes binding to recipient cell and releasing bioactive molecules, such as lipids, proteins, and nucleic acids. Of note, exosomes exert the remarkable effects on lipid metabolism, including the synthesis, transportation and degradation of the lipid. The disorder of lipid metabolism mediated by exosomes leads to the occurrence and progression of diseases, such as atherosclerosis, cancer, nonalcoholic fatty liver disease (NAFLD), obesity and Alzheimer's diseases and so on. More importantly, lipid metabolism can also affect the production and secretion of exosomes, as well as interactions with the recipient cells. Therefore, exosomes may be applied as effective targets for diagnosis and treatment of diseases.

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Cholesterol promotes the migration and invasion of renal carcinoma cells by regulating the KLF5/miR-27a/FBXW7 pathway

Cited by 46 publications

References 26 publications

Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells

Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells

Apolipoprotein C1 (APOC1): A Novel Diagnostic and Prognostic Biomarker for Clear Cell Renal Cell Carcinoma

The crosstalk: exosomes and lipid metabolism

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