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KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase.

ABSTRACT: The dysregulation of cellular metabolism, particularly lipid metabolism, is essential for cancer progress. Monoglyceride lipase (MGLL) is an important fatty acid metabolism enzyme, which converts monoacylglycerides to free fatty acids and glycerol. Despite the expression level of MGLL was reported to be downregulated in Hepatocellular carcinoma (HCC), the clinical significances and molecular mechanism of MGLL downregulation remains unknown. In the current study, the clinical significances of MGLL expression were investigated in 95 patients with HCC and the transcription factors of MGLL were identified in HCC cells. We found that MGLL was frequently downregulated in HCC samples, especially in metastatic tumor tissues. Patients with low MGLL expression owned remarkably lower 5 year-overall survival (5-OS). Functionally, we found that MGLL played an important role in HCC cell migration. Overexpression of MGLL suppressed cell migration and depletion of MGLL by shRNA promoted cell migration. Further studies indicated that KLF4 directly bound to the promoter of MGLL and accelerated MGLL expression, which then led to HCC cell migration decrease. Additionally, the expression levels of KLF4 were positive association with MGLL expression in HCC tissues. Collectively, our data suggest that KLF4 is a key regulator of MGLL. The KLF4-MGLL axis plays an essential role in suppressing HCC cell migration.

SUBMITTER: Yang X

PROVIDER: S-EPMC6048399 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase.

Yang Xuejun X Zhang Dongmei D Liu Sha S Li Xiaojie X Hu Wanglai W Han Chuanchun C

American journal of cancer research 20180601 6

The dysregulation of cellular metabolism, particularly lipid metabolism, is essential for cancer progress. Monoglyceride lipase (MGLL) is an important fatty acid metabolism enzyme, which converts monoacylglycerides to free fatty acids and glycerol. Despite the expression level of MGLL was reported to be downregulated in Hepatocellular carcinoma (HCC), the clinical significances and molecular mechanism of MGLL downregulation remains unknown. In the current study, the clinical significances of MGL ...[more]

PMID: 30034939

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Project description:Background: Hepatocellular carcinoma (HCC) presents a common malignant tumor worldwide. Although kinectin 1 (KTN1) is the most frequently identified antigen in HCC tissues, the detailed roles of KTN1 in HCC remain unknown. This study seeks to clarify the expression status and clinical value of KTN1 in HCC and to explore the complicated biological functions of KTN1 and its underlying mechanisms. Methods: In-house reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of KTN1 in HCC tissues. External gene microarrays and RNA-sequencing datasets were downloaded to confirm the expression patterns of KTN1. The prognostic ability of KTN1 in HCC was assessed by a Kaplan-Meier curve and a hazard ratio forest plot. The CRISPR/Cas9 gene-editing system was used to knock out KTN1 in Huh7 cells, which was verified by PCR-Sanger sequencing and western blotting. Assays of cell migration, invasion, viability, cell cycle, and apoptosis were conducted to explore the biological functions. RNA sequencing was performed to quantitatively analyze the functional deregulation in KTN1-knockout cells compared to Huh7-wild-type cells. Upregulated genes that co-expressed with KTN1 were identified from HCC tissues and were functionally annotated. Results: KTN1 expression was increased in HCC tissues (standardized mean difference [SMD] = 0.20 [0.04, 0.37]). High KTN1 expression was significantly correlated with poorer prognosis of HCC patients, and KTN1 may be an independent risk factor for HCC (pooled HRs = 1.31 [1.05, 1.64]). After KTN1-knockout, the viability, migration, and invasion ability of HCC cells were inhibited. The proportion of HCC cells in the G0-G1 phases increased after KTN1 knockout, which also elevated the apoptosis rates in HCC cells. Several cascades, including innate immune response, chemical carcinogenesis, and positive regulation of transcription by RNA polymerase II, were dramatically changed after KTN1 knockout. KTN1 primarily participated in the cell cycle, DNA replication, and microRNAs in cancer pathways in HCC tissues. Conclusion: Upregulation of KTN1 served as a promising prognosticator in HCC patients. KTN1 promotes the occurrence and deterioration of HCC by mediating cell survival, migration, invasion, cell cycle activation, and apoptotic inhibition. KTN1 may be a therapeutic target in HCC patients.

Dataset Information

KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase.

Publications

KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase.

Similar Datasets

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