Sequential Occurrence of Preneoplastic Lesions and Accumulation of Loss of Heterozygosity in Patients With Gallbladder Stones Suggest Causal Association With Gallbladder Cancer

Jain, Kajal; Mohapatra, Trilochan; Das, Prasenjit; Misra, Mahesh Chandra; Gupta, Siddhartha Datta; Ghosh, Manju; Kabra, Madhulika; Bansal, Virinder Kumar; Sreenivas, Vishnubhatla; Garg, Pramod Kumar

doi:10.1097/sla.0000000000000495

Cited by 50 publications

(41 citation statements)

References 23 publications

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“…However, a poor overlap exists between these biomarkers of gallbladder cancer. Thus, it might be a better resolution to establish more-accurate prognostic gene signatures by using a combination of different types of transcripts (24). A growing volume of literature has demonstrated that noncoding RNAs, predominantly miRNAs, could serve as potential biomarkers of gallbladder cancer (3,25).…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase–Dependent Cell Proliferation in Gallbladder Cancer

et al. 2016

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Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNAbinding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361-71. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase–Dependent Cell Proliferation in Gallbladder Cancer

et al. 2016

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“…Inactivation of the TP53 gene, either by deletion or mutation, is the most common genetic alteration observed across cancers at different anatomic sites [23], including GBC [24,25]. TP53 alterations are observed even in histologically normal epithelia from GDS patients with chronic cholecystitis, and the frequency of TP53 alterations increases as impairment of epithelial architecture progresses from metaplasia to invasive carcinoma [26,27]. Environmental exposures can lead to TP53 mutations and affect inflammatory and other immune responses.…”

Section: Inflammation and Cancermentioning

confidence: 99%

The inflammatory inception of gallbladder cancer

Espinoza

Bizama

García

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

115

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Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia–dysplasia–carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted.

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“…In a study by Jain and colleagues, the authors examined 350 gallbladder specimens from patients with gallstones, and found mucosal hyperplasia in 32%, metaplasia in 47.8%, dysplasia in 15.7%, and carcinoma in situ in 0.6% of specimens. 11 The authors were able to show loss of genetic heterozygosity in 2.1% to 47.8% of preneoplastic lesions at 8 different loci for several tumor suppressor genes associated with gallbladder cancer, but showed no loss of heterozygosity in normal gallbladders, thereby suggesting a possible mechanistic association between gallstones and gallbladder cancer beyond inflammation and neoplasia.…”

Section: Etiology and Pathogenesismentioning

confidence: 96%

Technical Aspects of Gallbladder Cancer Surgery

Qadan

Kingham

2016

Surgical Clinics of North America

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Sequential Occurrence of Preneoplastic Lesions and Accumulation of Loss of Heterozygosity in Patients With Gallbladder Stones Suggest Causal Association With Gallbladder Cancer

Abstract: Patients with gallstones had a high frequency of preneoplastic lesions and accumulation of LOH at various tumor suppressor genes, suggesting a possible causal association of gallstones with GBC.

Cited by 50 publications

References 23 publications

Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase–Dependent Cell Proliferation in Gallbladder Cancer

Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase–Dependent Cell Proliferation in Gallbladder Cancer

The inflammatory inception of gallbladder cancer

Technical Aspects of Gallbladder Cancer Surgery

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