Metabolic Perturbation and Potential Markers in Patients with Esophageal Cancer

Zhu, Xianlan; Wang, Kun; Liu, Gaoshuang; Wang, Yuqing; Xu, Jin; Liu, Linsheng; Li, Mengjie; Shi, Jian; Aa, Jiye; Yu, Ling

doi:10.1155/2017/5469597

Cited by 30 publications

(17 citation statements)

References 31 publications

(28 reference statements)

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“…5A) showed that of the 38 up-regulated metabolites in ZD:CTRL esophagus, about 1/3 (32%) were associated with metabolic alteration in amino acid (AA) metabolism. Differences in AA levels have been reported in many human cancers, including ESCC (35,36,40). Six AAs (lysine, histidine, proline, serine, tyrosine, glycine) are similarly up-regulated in human ESCC (36).…”

Section: Zd:ctrl Rat Esophagus Exhibits a Tumor-associated Metabolomementioning

confidence: 88%

“…Metabolomics analysis showed that the ESCC-bearing ZD:CTRL esophagus has a highly dysregulated metabolome, with 69 significantly altered metabolites. In particular, ∼32% of the up-regulated metabolites are implicated in active amino acid biosynthesis, a common feature of human ESCC (35,36,40). Phosphoenolpyruvate, the top down-regulated species in ZD:CTRL vs. ZS:CTRL esophagus (−5.83-fold, P = 0.010), is a metabolic checkpoint of antitumor T cell responses (47).…”

Section: Discussionmentioning

confidence: 99%

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Abrogation of esophageal carcinoma development in miR-31 knockout rats

Fong

Taccioli

Palamarchuk

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden followingN-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P= 0.038) and miR-31 gene knockout abrogated development of ESCC (P= 1 × 10−6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB–controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31–associated EGLN3/NF-κB–controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31−/−rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.

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Section: Zd:ctrl Rat Esophagus Exhibits a Tumor-associated Metabolomementioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Abrogation of esophageal carcinoma development in miR-31 knockout rats

Fong

Taccioli

Palamarchuk

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Metabolomics (of which lipidomics is a branch), is a promising field of systems biology that investigates the sets of metabolites and lipids present in biological systems. Therefore, metabolomics and lipidomics have been used to study the biomarkers of many human diseases, including esophageal cancer (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In this study, through primary screening of sensitive cancer cell lines, esophageal cancer was selected, and an untargeted lipidomic analysis based on an LC-MS/MS analysis of clinical samples (blood plasma samples from healthy volunteers and esophageal cancer patients, tumor tissues and paracancerous tissues from esophageal cancer patients), were performed to identify candidate lipid biomarkers in esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

Angustoline Inhibited Esophageal Tumors Through Regulating LKB1/AMPK/ELAVL1/LPACT2 Pathway and Phospholipid Remodeling

Zhang

et al. 2020

Front. Oncol.

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Esophageal cancer is a type of gastrointestinal carcinoma and is among the 10 most common causes of cancer death worldwide. However, the specific mechanism and the biomarkers in the proliferation and metastasis of esophageal tumors are still unclear. Therefore, the development of several natural products which could inhibit esophageal tumors deserve attention. In the present study, different sources of cancer cells were used to select the sensitive cell line (esophageal cancer cell KYSE450) and the proper dose of angustoline, which were utilized in the following cell viability, migration and invasion assays. Then the lipidomic detection of clinical samples (tissue and blood plasma) from esophageal cancer patients was performed, to screen out the specific phospholipid metabolites [PC (16:0/18:1) and LPC (16:0)]. Considering lysophosphatidylcholine acyltransferase 2 (LPCAT2) was tightly relative with phospholipids conversion, serine/threonine-protein kinase 11 (LKB1), 5 ′-monophosphate (AMP)-activated protein kinase (AMPK) and embryonic lethal, and abnormal vision, drosophila-like 1 (ELAVL1) were investigated, to evaluate their expression levels in esophageal tumor tissue and KYSE450 cells. Additionally, KYSE450 tumor bearing mouse model was constructed, the role of angustoline in inhibiting esophageal tumors through regulating LKB1/AMPK/ELAVL1/LPCAT2 pathway was validated, and found that the conversion from LPC (16:0) to PC (16:0/18:1) was blocked by angustoline in some degree. The above results for the first time proved that angustoline suppressed esophageal tumors through activating LKB1/AMPK and inhibiting ELAVL1/LPCAT2, which consequently blocked phospholipid remodeling from LPC (16:0) to PC (16:0/18:1).

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“…Cholesterol levels are higher in EC tissues compared to corresponding tumor-adjacent tissues [15]. To the best of our knowledge, few reports are available about the role of SCAP or cholesterol in the metastasis of EC.…”

Section: Introductionmentioning

confidence: 91%

GDF15-Mediated Cholesterol Metabolism Promotes EMT and Metastasis in Esophageal Cancer

Dong

Huang

Jiang

et al. 2020

Preprint

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Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings.Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo, knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

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Metabolic Perturbation and Potential Markers in Patients with Esophageal Cancer

Cited by 30 publications

References 31 publications

Abrogation of esophageal carcinoma development in miR-31 knockout rats

Abrogation of esophageal carcinoma development in miR-31 knockout rats

Angustoline Inhibited Esophageal Tumors Through Regulating LKB1/AMPK/ELAVL1/LPACT2 Pathway and Phospholipid Remodeling

GDF15-Mediated Cholesterol Metabolism Promotes EMT and Metastasis in Esophageal Cancer

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