Dataset Information

PKM2 enhances cancer invasion via ETS-1-dependent induction of matrix metalloproteinase in oral squamous cell carcinoma cells.

ABSTRACT: OBJECTIVES:This study aimed at investigating the molecular mechanism underlying PKM2-mediated cancer invasion. MATERIALS & METHODS:To optimize the investigation of PKM2-specific effects, we used two immortalized oral cell lines. The two cell lines drastically differed in PKM2 expression level, particularly in the level of nuclear PKM2, and subsequently in glucose metabolism and tumorigenicity. RESULTS:Knockdown of PKM2 reduced not only the glucose metabolism but also the invasive activity by curtailing the expressions of matrix metalloproteinases (MMP): PKM2 could modulate MMP-9 expression by regulating ETS-1 inside the nucleus. These results were further confirmed in an oral squamous cell carcinoma (OSCC) cell line. In correspondence with in vitro findings, clinicopathological data from OSCC patients indicated strong association between PKM2 expression and poor survival rate. Additionally, upon analysis of public database, significant positive correlation was found between PKM2 and ETS-1 in OSCC. CONCLUSION:Collectively, this study unveiled the molecular mechanism underlying PKM2-mediated cancer invasion, thereby providing novel targets for therapeutics development against invasive OSCC.

SUBMITTER: Park YJ

PROVIDER: S-EPMC6508653 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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PKM2 enhances cancer invasion via ETS-1-dependent induction of matrix metalloproteinase in oral squamous cell carcinoma cells.

Park Young-Jin YJ Kim Jue Young JY Lee Doo Young DY Zhang Xianglan X Bazarsad Shadavlonjid S Chung Won-Yoon WY Kim Jin J

PloS one 20190509 5

<h4>Objectives</h4>This study aimed at investigating the molecular mechanism underlying PKM2-mediated cancer invasion.<h4>Materials & methods</h4>To optimize the investigation of PKM2-specific effects, we used two immortalized oral cell lines. The two cell lines drastically differed in PKM2 expression level, particularly in the level of nuclear PKM2, and subsequently in glucose metabolism and tumorigenicity.<h4>Results</h4>Knockdown of PKM2 reduced not only the glucose metabolism but also the in ...[more]

PMID: 31071178

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Project description:BackgroundMounting evidence has suggested the essential role of long non-coding RNAs (lncRNAs) in a plethora of malignant tumors, including hepatocellular carcinoma. However, the underlyling mechanisms of lncRNAs remain unidentified in HCC. The present work was aimed to explore the regulatory functions and mechanisms of LncRNA LNCAROD in HCC progression and chemotherapeutic response.MethodsThe expression of LNCAROD in HCC tissues and cell lines were detected by quantitative reverse transcription PCR (qPCR). Cancer cell proliferation, migration, invasion, and chemoresistance were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and chemosensitivity assays. Methylated RNA immunoprecipitation qRCR (MeRIP-qPCR) was used to determine N6-methyladenosine (m6A) modification level. RNA immunoprecipitation (RIP) and RNA pull down were applied to identify the molecular sponge role of LNCAROD for modulation of miR-145-5p via the competing endogenous RNA (ceRNA) mechanism, as well as the interaction between LNCAROD and serine-and arginine-rich splicing factor 3 (SRSF3). The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and LNCAROD was also identified by RIP assay. Gain- or-loss-of-function assays were used to identify the function and underlying mechanisms of LNCAROD in HCC.ResultsWe found that LNCAROD was significantly upregulated and predicted a poorer prognosis in HCC patients. LNCAROD upregulation was maintained by increased m6A methylation-mediated RNA stability. LNCAROD significantly promoted HCC cell proliferation, migration, invasion, and chemoresistance both in vitro and in vivo. Furthermore, mechanistic studies revealed that pyruvate kinase isoform M2 (PKM2)-mediated glycolysis enhancement is critical for the role of LNACROD in HCC. According to bioinformatics prediction and our experimental data, LNCAROD directly binds to SRSF3 to induce PKM switching towards PKM2 and maintains PKM2 levels in HCC by acting as a ceRNA against miR-145-5p. The oncogenic effects of LNCAROD in HCC were more prominent under hypoxia than normoxia due to the upregulation of hypoxia-triggered hypoxia-inducible factor 1α.ConclusionsIn summary, our present study suggests that LNCAROD induces PKM2 upregulation via simultaneously enhancing SRSF3-mediated PKM switching to PKM2 and sponging miR-145-5p to increase PKM2 level, eventually increasing cancer cell aerobic glycolysis to participate in tumor malignancy and chemoresistance, especially under hypoxic microenvironment. This study provides a promising diagnostic marker and therapeutic target for HCC patients.

Dataset Information

PKM2 enhances cancer invasion via ETS-1-dependent induction of matrix metalloproteinase in oral squamous cell carcinoma cells.

Publications

PKM2 enhances cancer invasion via ETS-1-dependent induction of matrix metalloproteinase in oral squamous cell carcinoma cells.

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