Hyperglycemia and Cancer: A State-of-the-Science Review

Hammer, Marilyn J.; Storey, Susan; Hershey, Denise Soltow; Brady, Veronica; Davis, Ellen D.; Mandolfo, Natalie; Bryant, Ashley Leak; Olausson, Jill

doi:10.1188/19.onf.459-472

Cited by 25 publications

(18 citation statements)

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“…Our finding that older age was associated with glycemic variability in patients without T2D is consistent with others (Gude et al, 2017). Age-related cellular changes such as increased oxidative stress and cellular senescence are known risk factors for inflammation and hyperglycemia (Hammer et al, 2019) and may contribute to glycemic variability. In patients with T2D, glycemic variability was not associated with age.…”

Section: Associations Between Glycemic Variability and Demographic And Clinical Characteristicssupporting

confidence: 92%

Glycemic Variability Within 1 Year Following Surgery for Stage II–III Colon Cancer

Mandolfo

Berger

Struwe

et al. 2021

Biological Research For Nursing

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Objective: To examine glycemic variability within 1 month and 1 year following surgery among adult patients, with and without Type 2 Diabetes (T2D), treated for stage II-III colon cancer. Method: A retrospective analysis of electronic health record data was conducted. Glycemic variability (i.e., standard deviation [SD] and coefficient of variation [CV] of > 2 blood glucose measures) was assessed within 1 month and within 1 year following colon surgery. Chi-square (χ2), Fisher’s exact, and Mann-Whitney U tests were used for the analyses. Results: Among the sample of 165 patients with stage II–III colon cancer, those with T2D had higher glycemic variability compared to patients without T2D ( p < .001), with values within 1 month following surgery (SD = 44.69 mg/dL, CV = 27.4%) vs (SD = 20.55 mg/dL, CV = 17.53%); and within 1 year following surgery (SD = 45.04 mg/dL, CV = 29.04%) vs (SD = 21.36 mg/dL, CV = 18.6%). Associations were found between lower body mass index and higher glycemic variability (i.e., SD [r = −.413, p < .05] and CV [r = −.481, p < .01]) within 1 month following surgery in patients with T2D. Higher preoperative glucose was associated with higher glycemic variability (i.e., SD r = .448, p < .01) within 1 year in patients with T2D. Demographic and clinical characteristics were weakly associated with glycemic variability in patients without T2D. Conclusions: Patients with stage II–III colon cancer with T2D experienced higher glycemic variability within 1 month and within 1 year following surgery compared to those without T2D. Associations between glycemic variability and demographic and clinical characteristics differed by T2D status. Further research in prospective studies is warranted.

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Section: Associations Between Glycemic Variability and Demographic And Clinical Characteristicssupporting

confidence: 92%

Glycemic Variability Within 1 Year Following Surgery for Stage II–III Colon Cancer

Mandolfo

Berger

Struwe

et al. 2021

Biological Research For Nursing

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“…Therefore, targeting YAP and its ISGylation for hyperglycemic tumors may achieve promising therapeutic effects. This is not only limited to LUAD discussed in this study, but may also include liver, colorectal, breast, pancreatic cancer, and other tumors that are more closely related to hyperglycemia [ 48 ]. Therefore, further research on YAP promoting tumors through glucose metabolism is needed, which is conducive to the proposal of individualized tumor diagnosis and treatment.…”

Section: Discussionmentioning

confidence: 99%

YAP ISGylation increases its stability and promotes its positive regulation on PPP by stimulating 6PGL transcription

et al. 2022

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Yes-associated protein (YAP) activation is crucial for tumor formation and development, and its stability is regulated by ubiquitination. ISGylation is a type of ubiquitination like post-translational modification, whereas whether YAP is ISGylated and how ISGylation influences YAP ubiquitination-related function remains uncovered. In addition, YAP can activate glucose metabolism by activating the hexosamine biosynthesis pathway (HBP) and glycolysis, and generate a large number of intermediates to promote tumor proliferation. However, whether YAP stimulates the pentose phosphate pathway (PPP), another tumor-promoting glucose metabolism pathway, and the relationship between this stimulation and ISGylation needs further investigation. Here, we found that YAP was ISGylated and this ISGylation inhibited YAP ubiquitination, proteasome degradation, interaction with-beta-transducin repeat containing E3 ubiquitin-protein ligase (βTrCP) to promote YAP stability. However, ISGylation-induced pro-YAP effects were abolished by YAP K497R (K, lysine; R, arginine) mutation, suggesting K497 could be the major YAP ISGylation site. In addition, YAP ISGylation promoted cell viability, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor formation. YAP ISGylation also increased downstream genes transcription, including one of the key enzymes of PPP, 6-phosphogluconolactonase (6PGL). Mechanistically, YAP promoted 6PGL transcription by simultaneously recruiting SMAD family member 2 (SMAD2) and TEA domain transcription factor 4 (TEAD4) binding to the 6PGL promoter to activate PPP. In clinical lung adenocarcinoma (LUAD) specimens, we found that YAP ISGylation degree was positively associated with 6PGL mRNA level, especially in high glucose LUAD tissues compared to low glucose LUAD tissues. Collectively, this study suggested that YAP ISGylation is critical for maintaining its stability and further activation of PPP. Targeting ISGylated YAP might be a new choice for hyperglycemia cancer treatment.

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“…In tumorbearing mice, the transcriptional regulation of PCSK9 by glucose was found to enhance serum PCSK9 levels. In general, patients with cancer often show hyperglycemia due to various reasons (44), and the elevated PCSK9 expression increases the serum LDL levels, which can promote metastatic progression (17,40,44). Deng et al reported the correlation between LDL and esophageal cancer prognosis (45).…”

Section: Discussionmentioning

confidence: 99%

Association of Serum Anti-PCSK9 Antibody Levels with Favorable Postoperative Prognosis in Esophageal Cancer

et al. 2021

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BackgroundEsophageal cancer often appears as postoperative metastasis or recurrence after radical surgery. Although we had previously reported that serum programmed cell death ligand 1 (PD-L1) level correlated with the prognosis of esophageal cancer, further novel biomarkers are required for more precise prediction of the prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with the cholesterol metabolism. But there was no report of relationship between serum PCSK9 antibody and cancer. Therefore, we investigated whether anti-PCSK9 antibodies could be a novel biomarker for solid cancer.MethodsSerum levels of anti-PCSK9 antibodies and antigens in patients with solid cancer were analyzed using amplified luminescence proximity homogeneous assay-linked immunosorbent assay (AlphaLISA). The reactivity of serum antibodies against recombinant PCSK9 protein was investigated by Western blotting, and the expression of PCSK9 antigens in esophageal cancer tissues was examined by immunohistochemical staining.ResultsAlphaLISA showed that serum anti-PCSK9 antibody (s-PCSK9-Ab) levels were significantly higher in patients with esophageal cancer, gastric cancer, colorectal cancer, lung cancer, and breast cancer than in healthy donors, and patients with esophageal cancer had the highest levels. The presence of serum antibody in patients was confirmed by Western blotting. There was no apparent correlation between s-PCSK9-Ab and PCSK9 antigen levels. Immunohistochemical staining demonstrated the expression of PCSK9 antigen in both the cytoplasm and nuclear compartments of esophageal squamous cell carcinoma tissue but not in normal tissue. Compared with patients with low s-PCSK9-Ab levels, those with high s-PCSK9-Ab levels had a favorable postoperative prognosis after radical surgery for esophageal cancer. In the multivariate analysis, tumor depth and s-PCSK9-Ab level were identified as independent prognostic factors. In the univariate analysis of clinicopathological features, high PCSK9 antibody levels were not associated with sex, age, location, tumor depth, lymph node status, squamous cell carcinoma antigen, or p53-Ab, whereas they correlated significantly with PD-L1 levels, which were associated with unfavorable prognosis. Correlation between s-PCSK9-Ab and PD-L1 levels was also confirmed in the logistic regression analysis; therefore, low s-PCSK9-Ab levels could discriminate another poor prognosis group other than high-PD-L1 group.ConclusionsPatients with solid cancer had higher s-PCSK9-Ab levels than healthy donors. High s-PCSK9-Ab levels indicated better prognosis for overall survival after surgery in patients with esophageal cancer.

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Hyperglycemia and Cancer: A State-of-the-Science Review

Cited by 25 publications

References 0 publications

Glycemic Variability Within 1 Year Following Surgery for Stage II–III Colon Cancer

Glycemic Variability Within 1 Year Following Surgery for Stage II–III Colon Cancer

YAP ISGylation increases its stability and promotes its positive regulation on PPP by stimulating 6PGL transcription

Association of Serum Anti-PCSK9 Antibody Levels with Favorable Postoperative Prognosis in Esophageal Cancer

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