Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis

Hirose, Yuki; Nagahashi, Masayuki; Katsuta, Eriko; Yuza, Kizuki; Miura, Kiyonori; Sakata, Jun; Kobayashi, Takashi; Ichikawa, Hiroshi; Shimada, Yasuhiro; Kameyama, Hitoshi; McDonald, Kerry-Ann; Takabe, Kazuaki; Wakai, Toshifumi

doi:10.1038/s41598-018-29144-9

Cited by 18 publications

(14 citation statements)

References 58 publications

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“…The levels of SPHK1 in breast tumor tissues were found to be significantly higher than the adjacent normal tissues in both the cohorts. These observations are consistent with the recent study which reports increased expression of SPHK1 in biliary tract cancer in TCGA cohort 42 . High levels of SPHK1 were shown to enhance tumor formation in breast cancer MCF-7 cells 43 .…”

Section: Discussionsupporting

confidence: 93%

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Bhadwal¹,

Dahiya²,

Shinde³

et al. 2020

Sci Rep

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perturbations in lipid metabolic pathways to meet the bioenergetic and biosynthetic requirements is a principal characteristic of cancer cells. Sphingolipids (SpLs) are the largest class of bioactive lipids associated to various aspects of tumorigenesis and have been extensively studied in cancer cell lines and experimental models. the clinical relevance of SpLs in human malignancies however is still poorly understood and needs further investigation. in the present study, we adopted a UHpLc-High resolution (orbitrap) Mass spectrometry (HRMS) approach to identify various sphingolipid species in breast cancer patients. A total of 49 SPLs falling into 6 subcategories have been identified. Further, integrating the multivariate analysis with metabolomics enabled us to identify an elevation in the levels of ceramide phosphates and sphingosine phosphates in tumor tissues as compared to adjacent normal tissues. the expression of genes involved in the synthesis of reported metabolites was also determined in local as well as TCGA cohort. A significant upregulation in the expression of CERK and SPHK1 was observed in tumor tissues in local and tcGA cohort. Sphingomyelin levels were found to be high in adjacent normal tissues. Consistent with the above findings, expression of SGMS1 in tumor tissues was downregulated in tcGA cohort only. clinical correlations of the selected metabolites and their performance as biomarkers was also evaluated. Significant ROC and positive correlation with Ki67 index highlight the diagnostic potential and clinical relevance of ceramide phosphates in breast cancer.Dysregulation of lipid homeostasis has become an established hallmark of cancer. The cancer cells exploit lipid metabolic pathways in order to fulfil their demand for energy as well as biosynthetic precursors. Aberrations in lipid metabolism thus affects numerous cellular processes such as cell growth, proliferation, differentiation and cell survival 1 . Sphingolipids (SPLs), apart from the inceptive view of being considered as mere structural components, have evolved as crucial regulators of myriads of cellular functions. The primary elements of sphingolipid metabolism such as ceramide, ceramide 1-phosphate and sphingosine 1-phosphate have recently emerged as key regulators in cancer cell growth, proliferation, survival, migration and drug resistance 2-4 . Numerous studies have described the elementary role of ceramide and sphingosine 1-phosphate rheostat in various types of cancers such as lung, breast and colon. However, these studies have provided the mechanistic details of sphingolipid metabolism in cancer cell lines and experimental models 5-7 , while their role in human malignancies is still poorly understood and needs further elucidation.Breast cancer continues to remain the most common malignancy among women worldwide 8 . The diagnosis rate of breast cancer among Indian females is as high as 25.8 per 100,000 women with a mortality rate of 12.7 per 100,000 women 9 . Despite advancement in diagnostic and therapeutic modalities, th...

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Section: Discussionsupporting

confidence: 93%

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Bhadwal¹,

Dahiya²,

Shinde³

et al. 2020

Sci Rep

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“…Similarly, ABTL0812 induces impairment of Des-1 activity, resulting in the accumulation of Dh-Cer and activation of UPR response, which, in combination with TRIB3-mediated AKT/mTOR axis inhibition, triggers cytotoxic autophagy in CCA cells [158,160]. Interestingly, Des1 expression was found to be upregulated in CCA cell lines compared with their nontumor counterparts NHC3 cells [158], correlating with previous reports [184] where Des1 was found overexpressed in CCA tissue compared with normal biliary tract tissue. Cancer cells have evolved to use the UPR to survive the ER stress induced by the hostile conditions of the tumor microenvironment (hypoxia, low glucose, intracellular acidification, etc.…”

Section: Discussion and Future Perspectivessupporting

confidence: 83%

“…The downregulation of Beclin1 in different cancers could indicate that tumor development is closely related to Beclin1-induced autophagic cell death [178,184,185]. Beclin1 downregulation can significantly reduce autophagy to protect tumor cells from autophagic cell death, contributing to the continuous development of tumor cells [186].…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Pérez‐Montoyo

2020

Cells

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Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.

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“…Patients were divided into either MYC DNA amplified tumors (GISTIC: 2) or MYC DNA non-amplified tumors (GISTIC: from −2 to 1) according to the definition of the amplification in the cBioportal, and then were divided into either MYC mRNA high or low expressing tumors based on the MYC mRNA level using a cutoff point to divide the same proportion of MYC DNA amplified and non-amplified tumors in the whole cohort as well as in the TNBC cohort. Since TCGA and METABRIC are de-identified publicly available cohorts, institutional review board approval was waived, which was the case with previous publications [38][39][40][41].…”

Section: Data Acquisition and Pre-processingmentioning

confidence: 99%

High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer

Katsuta

Yan

Terauchi

et al. 2019

IJMS

Self Cite

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DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the targeted DNA-sequencing panels under the assumption of reflecting upregulated signaling. However, it remains unclear if MYC DNA amplification is a surrogate of its upregulated signaling. Thus, we investigated the difference between MYC DNA amplification and mRNA high expression in TNBCs utilizing publicly available cohorts. MYC DNA amplified tumors were found to have various mRNA expression levels, suggesting that MYC DNA amplification does not always result in elevated MYC mRNA expression. Compared to other subtypes, both MYC DNA amplification and mRNA high expression were more frequent in the TNBCs. MYC mRNA high expression, but not DNA amplification, was significantly associated with worse overall survival in the TNBCs. The TNBCs with MYC mRNA high expression enriched MYC target genes, cell cycle related genes, and WNT/β-catenin gene sets, whereas none of them were enriched in MYC DNA amplified TNBCs. In conclusion, MYC mRNA high expression, but not DNA amplification, reflects not only its upregulated signaling pathway, but also clinical significance in TNBCs.

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Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis

Cited by 18 publications

References 58 publications

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer

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