Development Of Gallbladder Cancer Research Articles

Gallbladder Carcinoma: A Review of Literature

Gallbladder cancer (GBC) is the most common cancer of the biliary tract but the sixth most common cancer of the gastrointestinal tract. This tumor has a very high death rate. It is impossible to emphasize how crucial early diagnosis is because GBC grows subtly when it is discovered later. A number of environmental and genetic factors have been linked to the beginning of GBC. Environmental variables such as cholelithiasis, chronic inflammation of the biliary tract, and parasite infections are known to have a substantial impact on the development of gallbladder cancer. Congenital causes include abnormalities in the pancreaticobiliary duct junction and biliary cysts. Over the last ten years, advancements in imaging technology coupled with a more aggressive and drastic surgical approach have enhanced patient outcomes and contributed to longer survival times for GBC patients. This review article focuses on the epidemiology of GBC, its risk factors, and clinical characteristics.

Microbiome dysbiosis in gallbladder cancer: A systemic review

Gallbladder cancer (GBC) starts in the epithelial tissue (lining of the bile duct and gallbladder). It is a type of aggressive cancer called adenocarcinoma that can spread to other tissues. Among all cases of biliary tract cancer, 50% is from GBC. It is a deadly cancer with a survival rate of 17.6% between 2007 and 2013. GBC is rarely found in the Western world, but it is commonly found in South Asia. In Southeast Asian countries, GBC plays a significant role in cancer-related morbidity and mortality. GBC incidence exhibits marked regional variability, a rare condition in the western population but having a higher frequency in India, especially the Indo-Gangetic belt and some northeast districts excluding Nagaland. This might be attributed to the differences in environmental factors and genetic predisposition modulating carcinogenesis. In GBC, only 10% of cases are identified in the early stages. The low rate of early detection is due to the lack of screening techniques and the aggressive characteristics of the tumor. Various risk factors are associated with GBC, for example, chronic cholecystitis with or without gallstones, obesity, exposure to heavy metals such as lead and arsenic, bacterial infection, congenital biliary cysts, and abnormal pancreaticobiliary duct junction. The risk factors can cause chronic gallbladder mucosa irritation, leading to dysplasia and neoplasia. GBC can form metaplasia to dysplasia in a time span of 5–15 years, then to carcinoma in situ, and finally to invasive cancer. Dysbiosis is responsible for various diseases, including cancer. Multiple triggers can cause dysbiosis, for example, environmental changes, inflammation, infection, medications, dietary changes, or genetic predisposition. Various researches show that Helicobacter pylori, human papillomavirus, Hepatitis B virus, and Hepatitis C virus microbial species can cause cancer. They are the major species responsible for 90% of infection-associated cancers. Various studies demonstrate that the strains of Salmonella and Helicobacter colonize are linked to developing GBC. While the mechanisms linking gut microbiota to GBC are not fully understood, several studies have suggested a potential association. According to a study, certain gut microbiomes, such as Fusobacterium nucleatum, found glut in GBC tissues, compared to adjacent normal tissues. By evaluating gut microbiome dysbiosis, we can see the potential link between gut microbiome dysbiosis and GBC; it may provide valuable insights into the development and progression of GBC. It could lead to the identification of new diagnostic markers and the development of novel therapeutic strategies. In GBC, the evaluation of gut microbiome dysbiosis (involving evaluating the composition, diversity, and functional capacity of the gut microbiome in patients) has emerged as a promising method for understanding the molecular mechanisms and identifying biomarkers for early prevention and detection of GBC and also investigating the possibility of any link between the gut microbiome and host immune response. In conclusion, evaluating gut microbiome dysbiosis in GBC is a promising direction for identifying potential early detection and prevention biomarkers. Additional investigation is therefore needed to determine the role of gut microbiome dysbiosis in the development and progression of GBC and to identify reliable biomarkers for clinical use.

Risk Factors and Prognostic Factors in GBC.

Background: Gallbladder cancer (GBC) is a rare entity with a poor prognosis, usually discovered late due to nonspecific symptoms; therefore, over the last years, attention has been focused on identifying the risk factors for developing this malignancy in order to provide an early diagnosis, as well as new prognostic factors in order to modulate the long-term evolution of such cases. The aim of this review is to discuss both major risk factors and prognostic factors in GBC for a better understanding and integration of relevant and currently available information. Methods: A literature search was performed using Cochrane Library, PubMed, Google Scholar, Elsevier, and Web of Science; studies published after the year of 2000, in English, were reviewed. Results: Over time, risk factors associated with the development of GBC have been identified, which outline the profile of patients with this disease. The most important prognostic factors in GBC remain TNM staging, safety margin, and R0 status, along with perineural invasion and lymphovascular invasion. Both the technique and experience of the surgeons and a pathological examination that ensures final staging are particularly important and increase the chances of survival of the patients. Conclusions: improvements in surgical techniques and pathological analyses might provide better and more consistent guidance for medical staff in the management of patients with GBC.

Identification of Long Noncoding RNAs Expression Profiles Between Gallstone and Gallbladder Cancer Using Next-Generation Sequencing Analysis.

Gallstone disease (GS) is an important risk factor for Gallbladder cancer (GBC). However, the mechanisms of the progression of GS to GBC remain unclear. Long non-coding RNA (lncRNA), modulates DNA/RNA/proteins at epigenetic, pre-transcriptional, transcriptional and posttranscriptional levels, and plays a potential therapeutic role in various diseases. This study aims to identify lncRNAs that have a potential impact on GS-promoted GBC progression. Six GBC patients without GS, six normal gallbladder tissues, nine gallstones and nine GBC patients with GS were admitted to our hospital. The next-generation RNA-sequencing was performed to analyze differentially expressed (DE) lncRNA and messenger RNA (mRNA) in four groups. Then overlapping and specific molecular signatures were analyzed. We identified 29 co-DEGs and 500 co-DElncRNAs related to gallstone or GBC. The intersection and concatenation of co-DEGs and co-DElncRNA functionally involved in focal adhesion, Transcriptional misregulation in cancers, Protein digestion and absorption, and ECM-receptor interaction signaling pathways may contribute to the development of gallbladder cancer. Further exploration is necessary for early diagnosis and the potential treatment of GBC. FXYD2, MPZL1 and PAH were observed in both co-DEGs and co-DElncRNA and validated by qRT-PCR. Our data identified a series of DEGs and DElncRNAs, which were involved in the progression of GBC and GS-related metabolism pathways. Compared to GBC, the GS profile was more similar to para-tumor tissues in transcriptome level and lower risk of cancer. Further exploration is necessary from GBC patients with different periods of follow-up gallstone.

Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer.

Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer. However, knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely limited. Here, by taking advantage of in situ Hi-C, RNA-sequencing, and chromatin immunoprecipitation sequencing (ChIP-seq), we investigated structural reorganization and functional changes in chromosomal compartments, topologically associated domains (TADs), and CCCTC binding factor (CTCF)-mediated loops in gallbladder cancer (GBC) tissues and cell lines. We observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression changes. Increased inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal controls. Furthermore, the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial-mesenchymal transition activation were enriched in cancer compared with their control counterparts. Cancer-specific enhancer-promoter loops, which contain multiple transcription factor binding motifs, acted as a central element to regulate aberrant gene expression. Depletion of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene expressions. Collectively, our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.

Updates and advances in the concept of gallbladder cancer treatment

The gallbladder is the most common site of tumor occurrence among biliary tract cancer. Gallbladder cancer accounts for approximately 0.6% of new cancers and 0.9% of cancer-related deaths. The risk factors identified for the development of gallbladder cancer include being female,>65 years of age, asymptomatic gallstone disease,and obesity. Surgical resection is the only curative treatment for early-stage gallbladder cancer, and some intermediate or advanced gallbladder cancers can be radically cured by extended resection. However, the extent of liver resection or lymph node dissection and whether to combine it with bile duct removal, revascularisation,and multiple organ resection remain somewhat controversial. After neoadjuvant treatment, up to a third of patients with locally advanced gallbladder cancer benefit from secondary surgical treatment. Only a small proportion of patients with gallbladder cancer at high risk for recurrence will benefit from postoperative adjuvant therapy. With the advent of different target-targeted drugs and the use of genetic tests in biliary tract cancer, targeted therapy and PD-1/PD-L1 inhibitors may become the new standard of care for gallbladder cancer and need to be further explored.

ELF3 suppresses gallbladder cancer development through downregulation of the EREG/EGFR/mTOR complex 1 signalling pathway.

The prognosis of gallbladder cancer (GBC) remains poor, and a better understanding of GBC molecular mechanisms is important. Genome sequencing of human GBC has demonstrated that loss-of-function mutations of E74-like ETS transcription factor 3 (ELF3) are frequently observed, with ELF3 considered to be a tumour suppressor in GBC. To clarify the underlying molecular mechanisms by which ELF3 suppresses GBC development, we performed in vivo analysis using a combination of autochthonous and allograft mouse models. We first evaluated the clinical significance of ELF3 expression in human GBC tissues and found that low ELF3 expression was associated with advanced clinical stage and deep tumour invasion. For in vivo analysis, we generated Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3f/f (KPCE) mice and Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3wt/wt (KPC) mice as a control and analysed their gallbladders histologically. KPCE mice developed larger papillary lesions in the gallbladder than those developed by KPC mice. Organoids established from the gallbladders of KPCE and KPC mice were analysed in vitro. RNA sequencing showed upregulated expression of epiregulin (Ereg) in KPCE organoids, and western blotting revealed that EGFR/mechanical targets of rapamycin complex 1 (mTORC1) were upregulated in KPCE organoids. In addition, ChIP assays on Elf3-overexpressing KPCE organoids showed that ELF3 directly regulated Ereg. Ereg deletion in KPCE organoids (using CRISPR/Cas9) induced EGFR/mTORC1 downregulation, indicating that ELF3 controlled EGFR/mTORC1 activity through regulation of Ereg expression. We also generated allograft mouse models using KPCE and KPC organoids and found that KPCE organoid allograft tumours exhibited poorly differentiated structures with mTORC1 upregulation and mesenchymal phenotype, which were suppressed by Ereg deletion. Furthermore, EGFR/mTORC1 inhibition suppressed cell proliferation and epithelial-mesenchymal transition in KPCE organoids. Our results suggest that ELF3 suppresses GBC development via downregulation of EREG/EGFR/mTORC1 signalling. EGFR/mTORC1 inhibition is a potential therapeutic option for GBC with ELF3 mutation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The inverse association between fasting blood glucose and the occurrence of gallbladder cancer in type 2 diabetes mellitus patients: a case-control study.

This study aimed to explore the correlation between diabetes mellitus (DM) and gallbladder cancer (GBC) in an epidemiological setting. The study summarized the clinical and laboratory data of 2210 GBC Chinese patients in the authors' hospital. A total of 17 influencing factors for GBC, including gender, body mass index (BMI), fasting blood glucose (FBG), fasting insulin (FINS), the homeostasis model assessment of insulin resistance (HOMA-IR), retinol-binding protein 4 (RBP4), and lipid indexes were analyzed using unconditional logistic regression analysis. Based on the results of univariate logistic regression, the risk of GBC was significantly and positively correlated with serum triglyceride, low-density lipoprotein, FINS, HOMA-IR, being female, BMI, DM, non-alcoholic fatty liver disease, and gallbladder stone disease (GSD), and significantly negatively correlated with high-density lipoprotein and FBG concentrations in serum, as well as hypertension. According to multivariate analysis, FINS was significantly positively associated with GBC risk, while DM showed an insignificant negative association; FBG was also not important. The most significant independent factor of GBC risk in patients with DM was HOMA-IR. Fasting blood glucose levels showed a significant negative relationship with GBC in patients with DM. In addition, this study indicated a significantly negative association between serum RBP levels and GBC. The findings of the current study revealed that the efficient treatment of insulin resistance is an important approach for decreasing GBC risk, as opposed to lowering blood sugar only, particularly in patients with DM. Interestingly, FBG may have had an inverse association with the development of GBC in patients with type 2 DM. Of note, the study found that a dramatic initial drop in RBP may help predict the occurrence of GBC.

Aprepitant inhibits the development and metastasis of gallbladder cancer via ROS and MAPK activation

BackgroundAprepitant, as a neurokinin-1 receptor (NK-1R) antagonist, originally applied for curing chemotherapy-induced nausea and vomiting, has been reported to have significant antitumor effect on several malignant tumors. However, the effect of aprepitant on gallbladder cancer (GBC) is not clear yet. This study aimed to investigate the anti-tumor activity of aprepitant on GBC and the potential mechanisms.MethodsThe NK-1R expression of gallbladder cancer cells were examined by immunofluorescence. MTT assay, wound healing and transwell migration assay were applied to detect the effect of aprepitant on cell proliferation, migration and invasion. Flow cytometry was used to detect the apoptosis rate. The effects of aprepitant on the expressions of cytokine were examined by real-time quantitative PCR and MAPK activation were detected via immunofluorescence and western blotting. Besides, xenograft model was established to investigate the effect of aprepitant in vivo.ResultsOur results indicated that NK‐1R was markedly expressed in gallbladder cancer cells and aprepitant effectively inhibited the proliferation, migration and invasion. Furthermore, the apoptosis, ROS and inflammation response were significantly boosted by aprepitant in GBC. Aprepitant induced NF‐κB p65 nuclear translocationin and increased the expressions of p-P65, p-Akt, p-JNK, p-ERK and p-P38, as well as the mRNA levels of inflammatory cytokines IL-1β, IL-6 and TNF-α. Consistently, aprepitant suppressed the growth of GBC in xenograft mice model.ConclusionOur study demonstrated that aprepitant could inhibit the development of gallbladder cancer via inducing ROS and MAPK activation, which suggested that aprepitant may become a promising therapeutic drug against GBC.

RNA sequencing revealed the multi-stage transcriptome transformations during the development of gallbladder cancer associated with chronic inflammation.

Gallbladder cancer (GBC) is a highly malignant tumor with extremely poor prognosis. Previous studies have suggested that the carcinogenesis and progression of GBC is a multi-stage and multi-step process, but most of them focused on the genome changes. And a few studies just compared the transcriptome differences between tumor tissues and adjacent noncancerous tissues. The transcriptome changes, relating to every stage of GBC evolution, have rarely been studied. We selected three cases of normal gallbladder, four cases of gallbladder with chronic inflammation induced by gallstones, five cases of early GBC, and five cases of advanced GBC, using next-generation RNA sequencing to reveal the changes in mRNAs and lncRNAs expression during the evolution of GBC. In-depth analysis of the sequencing data indicated that transcriptome changes from normal gallbladder to gallbladder with chronic inflammation were distinctly related to inflammation, lipid metabolism, and sex hormone metabolism; transcriptome changes from gallbladder with chronic inflammation to early GBC were distinctly related to immune activities and connection between cells; and the transcriptome changes from early GBC to advanced GBC were distinctly related to transmembrane transport of substances and migration of cells. Expression profiles of mRNAs and lncRNAs change significantly during the evolution of GBC, in which lipid-based metabolic abnormalities play an important promotive role, inflammation and immune activities play a key role, and membrane proteins are very highlighted molecular changes.

Heterodimerization of cholecystokinin 1 and cholecystokinin 2 receptors in gallbladder cancer: a new mechanism for carcinogenesis.

Cholecystokinin is present in abundance in gallbladder tissue and mediates function through two structurally related receptors, CCK1R and CCK2R. Heterodimerization of these receptors is known to impact cell growth in vitro. However, the significance of these heterodimers in gallbladder carcinogenesis is relatively unknown. Therefore, we evaluated the expression and the dimerization status of CCK1 and CCK2 receptors in human gallbladder carcinoma cell line (GBC-SD) and resected gallbladder tissue from normal (n = 10), cholelithiasis (n = 25) and gallbladder cancer (n = 25) by immunofluorescence/immunohistochemistry and western blot. The dimerization status of CCK1R and CCK2R was evaluated by co-immunoprecipitation. To understand the effect of heterodimerization of these receptors on growth-related signaling pathways, the expression of p-AKT, rictor, raptor and p-ERK was evaluated by western blot. We demonstrated the expression and heterodimerization of CCK1 and CCK2 receptor in GBC-SD gall bladder carcinoma cell line. Knockdown of CCK1R and CCK2R in the cell line led to significant reduction in p-AKT (P = 0.005; P = 0.0001) and rictor (P < 0.001; P < 0.001) levels. In tissue samples, significantly higher expression of CCK1R and CCK2R was observed in gallbladder cancer when compared to other groups both by immunohistochemistry (P = 0.008 and P = 0.013) and western blot (P = 0.009 and P = 0.003). An increase in heterodimer formation of CCK1R with CCK2R was observed in gallbladder cancer when compared to normal and cholelithiasis tissues. No significant difference in the expression of p-AKT and p-ERK was observed between the three groups. Our results provide the first evidence of heterodimerization of CCK1R and CCK2R in gallbladder tissue, and its association with development of gallbladder cancer. This finding has potential clinical and therapeutic significance.

Investigating the Relationship between Gallbladder Malignancy and Various Factors in Surgically Treated Gallbladder Disease Patients

Introduction: Gallbladder cancer is a rare but aggressive disease with a poor prognosis. Factors that may contribute to the development of gallbladder cancer include chronic inflammation, gallstones, and obesity. This study will examine the prevalence of these factors in patients who have undergone surgery for gallbladder disease, and determine if there is a correlation with the development of gallbladder cancer. This information will be valuable in identifying high-risk individuals and developing strategies for the early detection and prevention of gallbladder cancer. Methods: This prospective cross-sectional and observational study was carried out in the Department of General Surgery and Hepato-Biliary-Pancreatic surgery, BIRDEM General Hospital, Dhaka from August 2019 to February 2021. Patients admitted to the General Surgery and Hepato-Biliary-Pancreatic Surgery Department of BIRDEM hospital who underwent gallbladder surgery were recruited for this study. Consecutive sampling was done in this study. Result: The present study findings showed that the majority (65.45%) of the participants were between the age of 50-59 years, with 38.18% being male and 61.82% being female. The most common comorbidities were diabetes (62.73%), hypertension (43.64%) and anaemia (40%). The most common clinical presentation was abdominal pain (76.36%) and the most common histopathological diagnosis was chronic calculous cholecystitis (49.09%), while 20% of participants had gallbladder carcinoma. The study found an association between age, gallbladder wall thickness and gallbladder malignancy. Participants who were 60 years or older were 4.865 times more likely to have gallbladder carcinoma and those with severe wall thickness (&gt;10mm) were 13.32 times more likely to have gallbladder carcinoma. Conclusion: The present study found that the majority of participants were between the age of 50-59 years, with a higher female prevalence. The most common comorbidities were diabetes, ..........

Non-coding RNAs as potential biomarkers of gallbladder cancer.

Gallbladder cancer (GBC) performs strongly invasive and poor prognosis, and adenocarcinoma is the most common histological type in it. Statistically, the 5-year survival rate of patients with advanced GBC is less than 5%. Such dismal outcome might be caused by chemotherapy resistance and native biology of tumor cells, regardless of emerging therapeutic strategies. Early diagnosis, depending on biomarkers, receptors and secretive proteins, is more important than clinical therapy, guiding the pathologic stage of cancer and the choice of medication. Therefore, it is in urgent need to understand the specific pathogenesis of GBC and strive to find promising novel biomarkers for early screening in GBC. Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs, miRs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are confirmed to participate in and regulate the occurrence and development of GBC. Exceptionally, lncRNAs and circRNAs could act as competing endogenous RNAs (ceRNAs) containing binding sites for miRNAs and crosstalk with miRNAs to target regulatory downstream protein-coding messenger RNAs (mRNAs), thus affecting the expression levels of specific proteins to participate in and regulate the development and progression of GBC. It follows that ncRNAs may become promising biomarkers and potential therapeutic targets for GBC. In this review, we mainly summarize the recent research progress of miRNAs and lncRNAs in regulating the development and progression of GBC, chemoresistance, and predicting the prognosis of patients, and highlight the potential applications of the lncRNA/circRNA-miRNA-mRNA cross-regulatory networks in early diagnosis, chemoresistance, and prognostic evaluation, aiming to better understand the pathogenesis of GBC and develop new diagnostic and therapeutic strategies.

A Review of the Etiology and Epidemiology of Gallbladder Cancer: What You Need to Know.

Gallbladder cancer (GBC) is the sixth most prevalent cancer of the gastrointestinal system but the most prevalent cancer of the biliary tract. This tumor is a highly fatal condition. The importance of early diagnosis cannot be overstated because GBC develops quietly with late detection. Several genetic and environmental variables have been associated with the onset of GBC. Cholelithiasis and chronic inflammation from the biliary tract and parasite infections are prime examples of environmental factors that significantly influence the development of GBC. Abnormal pancreaticobiliary duct junction and biliary cysts are examples of congenital causes. In the past decade, new imaging technologies and a more radical and aggressive surgical approach have improved patient outcomes and aided prolonged survival for GBC patients. This review article focuses on the epidemiology of GBC, its risk factors, and clinical characteristics.

Unravelling of the comparative Transcriptomic Profile of Gallbladder Cancer using mRNA sequencing.

Gallbladder cancer (GBC) represents a wide geographical diversity as well as heterogeneity in clinical and genomic landscape. There seems to be little progress in the development of diagnostic biomarkers, targeted therapies or individualized approaches to GBC management. In this study, we investigated the whole transcriptome profile of GBC patients using RNA sequencing and identified key genes and pathways associated with gallbladder cancer using bioinformatics. A total of 10 cases of GBC were collected and sequenced. The raw reads of the gallbladder sample was compared with the gallbladder normal control (SRA Database ID: ERX288537: HPA RNA-seq normal tissues gallbladder). Using Gene ontology analysis the differentially expressed genes were categorized into the biological pathway, cellular component, and molecular function. Pathway enrichment analyses, protein-protein interaction, transcription factor and miRNA interaction that regulate the expression of hub genes were conducted using bioinformatics tool. A total of 954 differentially expressed mRNA transcripts were identified, including overexpression of REG4, TMEM238, S100A2, LYPD2, and KRT17, as well as underexpressed genes like CCKAR, IGSF10, CHRM2, CRISP3, and FGF19. Enrichment analysis showed the metabolic pathways to be the top five cancer pathways in gallbladder carcinogenesis besides PI3k-Akt signalling pathway, cAMP signalling pathway, miRNAs in cancer, and cell adhesion profile of GBC. CCKAR, CDKN2A and LRRK2 were found to be most involved genes in its progression and development through different regulatory pathways. Further, most of the genes were significantly involved in PI3k-Akt, Wnt and hedgehog signaling pathways which have a key role in gallbladder cancer development.

IL4Rα and IL13Rα1 Are Involved in the Development of Human Gallbladder Cancer.

Background: Gallbladder cancer is commonly associated with inflammation, which indicates that inflammation-related cytokines and cytokine receptors are related to the progression of gallbladder cancers. Interleukin 4 (IL4) is a well-known cytokine that promotes the differentiation of naive helper T cells (Th0) to T helper type 2 cells (Th2). IL13 is a cytokine that is secreted by Th2 cells. IL4 and IL13 are closely related in immune responses. However, the role of IL4Rα and IL13Rα1 signaling pathway has not been fully understood in the development of gallbladder cancer. Methods: In human gallbladder carcinomas, the expression of IL4Rα and IL13Rα1 were evaluated with immunohistochemical staining in tissue microarray tissue sections. After knockdown of IL4Rα or IL13Rα1, cell assays to measure the proliferation and apoptosis and Western blotting analysis were conducted in SNU308 human gallbladder cancer cells. Since Janus kinases2 (JAK2) was considered as one of the down-stream kinases under IL4Rα and IL13Rα1 complex, the same kinds of experiments were performed in SNU308 cells treated with AZD1480, Janus-associated kinases2 (JAK2) inhibitor, to demonstrate the cytotoxic effect of AZD1480 in SNU308 cells. Results: Immunohistochemical expression of IL4Rα was significantly associated with the expression of IL13Rα1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4Rα, cytoplasmic expression of IL4Rα, nuclear expression of IL13Rα1, and cytoplasmic expression of IL13Rα1 were significantly associated with shorter overall survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4Rα as an independent poor prognostic indicator of overall survival and relapse-free survival. Then, we found that knockdown of IL4Rα or IL13Rα1 decreased viability and induced apoptosis in SNU308 cells via activation of FOXO3 and similarly, AZD1480 decreased viability and induced apoptosis in SNU308 cells with dose dependent manner. Conclusions: Taken together, our results suggest that IL4Rα and IL13Rα1 might be involved in the development of human gallbladder cancer cells and IL4Rα and IL13Rα1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment.

Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer.

Gallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet. Other risk factors such as autoimmune disorders and bacterial, parasitic and fungal infections have also been described. All these factors can generate a long-term inflammatory state characterized by the persistent activation of the immune system, the frequent release of pro-inflammatory cytokines, and the constant production of reactive oxygen species that result in a chronic damage/repair cycle, subsequently inducing the loss of the normal architecture of the gallbladder mucosa that leads to the development of GBC. This review addresses how the different risk factors could promote a chronic inflammatory state essential to the development of gallbladder carcinogenesis, which will make it possible to define some strategies such as anti-inflammatory drugs or public health proposals in the prevention of GBC.

Tumor suppressive lncRNA MEG3 binds to EZH2 and enhances CXCL3 methylation in gallbladder cancer.

Gallbladder cancer is a malignant tumor with a high mortality rate. Accumulating evidence supports that lncRNA MEG3 may halt the progression of gallbladder cancer, while the downstream mechanism is rarely studied. Thus, we aim to investigate the molecular basis of the tumor-suppressing role of lncRNA MEG3 in gallbladder cancer. The expression of lncRNA MEG3 and CXCL3 was measured in patient serum and cell lines of gallbladder cancer. The viability, apoptosis, migration, and invasion of gallbladder cancer cells were assessed following ectopic MEG3 expression, as detected by CCK-8, flow cytometry, and Transwell assays. The interaction among lncRNA MEG3, EZH2, and CXCL3 was explored through ChIP, RNA pull-down, and RIP assays. The effects of lncRNA MEG3 and CXCL3 on tumor growth were evaluated by a mouse xenograft model. lncRNA MEG3 was expressed at a low level in gallbladder cancer patient serum and cell lines, while CXCL3 was highly expressed. MEG3 overexpression repressed the malignant behaviors of gallbladder cancer cells and promoted their apoptosis. MEG3 was mainly localized in the nucleus. MEG3 bound to EZH2, and EZH2 catalyzed the H3K27 trimethylation of the CXCL3 promoter region. MEG3 downregulated CXCL3 by activating EZH2-mediated H3K27 trimethylation of CXCL3; MEG3 overexpression attenuated cancer cell malignant behaviors in vitro and suppressed tumor growth in vivo in gallbladder cancer by inhibiting CXCL3 expression. Altogether, our results indicate that lncRNA MEG3 impedes gallbladder cancer development via the EZH2-CXCL3 axis, offering potential biomarkers for gallbladder cancer management.

An Integrative Systems Biology Approach Identifies Molecular Signatures Associated with Gallbladder Cancer Pathogenesis

Gallbladder cancer (GBC) has a lower incidence rate among the population relative to other cancer types but is a major contributor to the total number of biliary tract system cancer cases. GBC is distinguished from other malignancies by its high mortality, marked geographical variation and poor prognosis. To date no systemic targeted therapy is available for GBC. The main objective of this study is to determine the molecular signatures correlated with GBC development using integrative systems level approaches. We performed analysis of publicly available transcriptomic data to identify differentially regulated genes and pathways. Differential co-expression network analysis and transcriptional regulatory network analysis was performed to identify hub genes and hub transcription factors (TFs) associated with GBC pathogenesis and progression. Subsequently, we assessed the epithelial-mesenchymal transition (EMT) status of the hub genes using a combination of three scoring methods. The identified hub genes including, CDC6, MAPK15, CCNB2, BIRC7, L3MBTL1 were found to be regulators of cell cycle components which suggested their potential role in GBC pathogenesis and progression.

Gallbladder clear cell carcinoma: A case report

Worldwide, the highest incidence rates (up to 7.5 per 100,000 in male and 23 per 100,000 in female) occur among populations in the Western part of South America (Chile and Peru), in North American Indians, in Mexican Americans, and in Northern India. The best characterized risk factor for the development of gallbladder cancer is chronic inflammation associated with gallstones. Metastatic clear cell carcinoma in the gallbladder is extremely rare, with reported frequencies of less than 0.6% in large autopsy reviews. Patient was a 54 year old female. Patient was right upper abdominal pain and epigastric middle pain. Nausea and vomiting, pain was started 10 days ago, after ate dumplings. No history of previous any gastrointestinal disease. The physical examination: Tenderness in right hypochondrium. Lump in the hypochondrium. Murphy's sign was positive. The patient's in blood test increased white blood cell and C-reactive protein. Abdominal ultrasound examination: Gallbladder is enlargement, about 6.0 cm × 3.0 cm like the mudstone in the gallbladder. GB wall thickening/double, common bile duct is dilated 1.2 cm. Abdominal contrast computed tomography examination: Moderate thickening with surrounding mild edematous changes in wall of the gallbladder. Size of the GB is moderated dilated with diffuse. We were emergency surgery of under general anesthesia open cholecystectomy and intraoperative cholangiogram. During surgery gallbladder was distended and gallbladder wall very thickness, hardness. In cholangiogram common bile duct no obstructive sign. Clear cell carcinoma very rare disease. Our team diagnosed during surgery and histological analysis.