BACKGROUND: Growing evidence suggests that long non-coding RNAs (lncRNAs) exert pivotal roles in fostering chemoresistance across diverse tumors. Nevertheless, the precise involvement of lncRNAs in modulating chemoresistance within the context of gallbladder cancer (GBC) remains obscure. This study aimed to uncover how lncRNAs regulate chemoresistance in gallbladder cancer, offering potential targets to overcome drug resistance. METHODS: To elucidate the relationship between gemcitabine sensitivity and small nucleolar RNA host gene 1 ( SNHG1 ) expression, we utilized publicly available GBC databases, GBC tissues from Renji Hospital collected between January 2017 and December 2019, as well as GBC cell lines. The assessment of SNHG1, miR-23b-3p, and phosphatase and tensin homolog (PTEN) expression was performed using in situ  hybridization, quantitative real-time polymerase chain reaction, and western blotting. The cell counting kit-8 (CCK-8) assay was used to quantify the cell viability. Furthermore, a GBC xenograft model was employed to evaluate the impact of SNHG1 on the therapeutic efficacy of gemcitabine. Receiver operating characteristic (ROC) curve analyses were executed to assess the specificity and sensitivity of SNHG1. RESULTS: Our analyses revealed an inverse correlation between the lncRNA SNHG1 and gemcitabine resistance across genomics of drug sensitivity in cancer (GDSC) and Gene Expression Omnibus (GEO) datasets, GBC cell lines, and patients. Gain-of-function investigations underscored that SNHG1 heightened the gemcitabine sensitivity of GBC cells in both in vitro and in vivo  settings. Mechanistic explorations illuminated that SNHG1 could activate PTEN -a commonly suppressed tumor suppressor gene in cancers-thereby curbing the development of gemcitabine resistance in GBC cells. Notably, microRNA (miRNA) target prediction algorithms unveiled the presence of miR-23b-3p binding sites within SNHG1 and the 3'-untranslated region (UTR) of PTEN . Moreover, SNHG1 acted as a sponge for miR-23b-3p, competitively binding to the 3'-UTR of PTEN , thereby amplifying PTEN expression and heightening the susceptibility of GBC cells to gemcitabine. CONCLUSION The SNHG1/miR-23b-3p/PTEN axis emerges as a pivotal regulator of gemcitabine sensitivity in GBC cells, holding potential as a promising therapeutic target for managing GBC patients.
Humans ; Deoxycytidine/pharmacology* ; PTEN Phosphohydrolase/genetics* ; Gemcitabine ; RNA, Long Noncoding/metabolism* ; MicroRNAs/genetics* ; Gallbladder Neoplasms/genetics* ; Cell Line, Tumor ; Animals ; Mice ; Drug Resistance, Neoplasm/genetics* ; Mice, Nude ; Antimetabolites, Antineoplastic ; Gene Expression Regulation, Neoplastic

Afatinib ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoembryonic Antigen ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Gallbladder Neoplasms ; drug therapy ; pathology ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Neoplasm Staging ; Tomography, X-Ray Computed

BACKGROUNDCurrently, all frequently used staging systems in gallbladder cancer (GBC) are based on postoperative pathological examinations. In patients undergoing curative operation, there is no effective method to predict survival preoperatively. In this study, we explored whether a combined utilization of two tumor biomarkers, namely carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA), could give a preoperative prediction of survival in resectable GBC.

METHODSSeventy-three patients who underwent radical resection for GBC were included in this study. A retrospective analysis of clinical-pathological data was conducted.

RESULTSBy multivariate analysis, CA 19-9 elevation (P < 0.05) and CEA elevation (P < 0.001) were discovered as two individual factors for postoperative survival. By a combined utilization, patients were divided into three groups: patients with elevation of CEA (group I), patients with elevation of CA 19-9 but without CEA (group II), and patients with nonelevations of either CA 19-9 or CEA (group III). The cumulative 5-year survival rates in groups I, II, and III were 0, 14.0%, and 42.8%, respectively (P < 0.05).

CONCLUSIONSBy a combined utilization of CA 19-9 and CEA, individualized prediction of survival is available in resectable GBC before operation. Extended radical operation brings the most prognostic benefits in patients with nonelevations of either CA 19-9 or CEA. However, if operation would be in a larger-scale destructive manner, careful consideration of surgical decisions should be made in patients with elevation of tumor biomarkers, especially CEA.

Adult ; Aged ; Aged, 80 and over ; CA-19-9 Antigen ; metabolism ; Carcinoembryonic Antigen ; metabolism ; Female ; Gallbladder Neoplasms ; metabolism ; mortality ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Retrospective Studies

BACKGROUNDFarnesoid X receptor (FXR) regulates tumorigenesis, but its clinical significance in gallbladder cancer (GBC) remains unclear. This study investigated its clinical and prognostic significance in GBC patients, as well as its association with the anti-apoptotic protein, myeloid cell leukemia sequence 1 (MCL1) protein.

METHODSFXR and MCL1 expression in 42 primary GBC and 15 normal gallbladder tissues were analyzed by immunohistochemistry. The patients and samples were collected from Ren Ji Hospital from January 2005 to December 2010. Their association with clinicopathologic factors and prognosis, as well as the correlation between FXR and MCL1 protein expression were analyzed by statistical analyses.

RESULTSCompared with normal gallbladder tissues, FXR expression was decreased and MCL1 expression was increased in GBC, during progression of tumor node metastasis (TNM) stage. The Kaplan-Meier survival analysis showed that FXR low-expression and MCL1 over-expression were significantly associated with overall poor survival. Furthermore, multivariate analysis showed that FXR and MCL1 are both prognostic factors for GBC patients. FXR low-expression was significantly correlated with MCL1 over-expression.

CONCLUSIONFXR might be a new molecular marker to predict the prognosis of patients with GBC and a novel therapeutic target.

Adult ; Aged ; Aged, 80 and over ; Disease Progression ; Female ; Gallbladder Neoplasms ; diagnosis ; metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Myeloid Cell Leukemia Sequence 1 Protein ; metabolism ; Neoplasm Staging ; Prognosis ; Receptors, Cytoplasmic and Nuclear ; metabolism

OBJECTIVETo investigate the difference in conjugated bile acids in the gallbladder bile between gallbladder cholesterol polyps and adenomatous polyps patients, and screen the differential diagnosis-markers for polypoid lesions of gallbladder (PLG).

METHODSFrom January to June 2013, the 20 cholesterol polyps patients, 10 adenomatous polyps patients and 10 patients without gallbladder diseases were enrolled. High performance liquid chromatography assay with ultraviolet detection was used to test 8 conjugated bile acids in gallbladder bile.

RESULTSThe 8 conjugated bile acids were completely analyzed in 10 minutes, and the assay was liner in the range 8-500 µg/ml. The correlation coeffients for linear regression was from 0.9996-0.9999 and the detection limits ranged from 3.90-7.81 µg/ml. The level of taurocholic acid (TCA) in adenomatous polyps group ((75 ± 51) µg/ml) was significantly lower than that in the cholesterol polyps ((228 ± 206) µg/ml, q = 3.120, P = 0.014) and control groups ((104 ± 40) µg/ml, q = 2.950, P = 0.027). The level of taurochenodeoxycholic acid (TCDCA) in cholesterol polyps group ((604 ± 444) µg/ml) was significantly higher than that in the adenomatous polyps ((310 ± 182) µg/ml, q = 2.560, P = 0.048) and control groups ((308 ± 21) µg/ml, q = 2.970, P = 0.023).

CONCLUSIONSThe levels of TCA and TCDCA in the gallbladder biles in cholesterol polyps patients were higher than those in adenomatous polyps patients, which may be the differential diagnosis-markers for PLG.

Adenocarcinoma ; diagnosis ; Adult ; Aged ; Bile ; chemistry ; Bile Acids and Salts ; analysis ; Case-Control Studies ; Diagnosis, Differential ; Female ; Gallbladder Diseases ; diagnosis ; metabolism ; Humans ; Male ; Middle Aged ; Polyps ; diagnosis ; metabolism ; Young Adult

To observe the effect of various doses of oil of Piper longum unsaponifiable matter (OPUM) to cholesterol gallstones in experimental mice. C57BL/6 mice (n = 60) were randomly divided into 6 groups: control group, model group, OPUM (15, 30 and 60 mg x kg(-1)) group and ursodeoxycholic acid (UDCA, 60 mg x kg(-1)) group, administered for 10 weeks. The level of serum lipid and liver function enzymes were tested. The gallbladder was removed and bile was obtained by centrifugation. Next, the levels of the bile total cholesterol (TC), phospholipid (PL) and bile acid (TBA) were measured. The indicators of lipid peroxidation were determined and cholesterol saturation index (CSI) was calculated. The liver histological changes were observed by HE staining. The results showed that serum TC, TG (triglycerides) and AST (aspartate transaminase) contents, gallbladder cholesterol crystallization and CSI increased significantly (P < 0.05). In addition, the activity of SOD decreased significantly and MDA content increased significantly in liver (P < 0.05). HE staining results showed that the hepatic cord disorder and intracellular lipid droplets increased significantly. All results indicate that lithogenic diet lead to the formation of cholesterol gallstones. In OPUM (30 and 60 mg x kg(-1)) group, serum TC, TG and AST content, gallbladder cholesterol crystallization and CSI decreased significantly, the activity of SOD increased significantly and MDA content decreased significantly. HE staining results showed that OPUM can improve the morphology of liver cell, reduce the degree of hepatic cord disorders and restore the cell morphology close to normal. The cause of OPUM prevents cholesterol gallstone formation maybe due to protect the integrity of the liver cells, lower CSI, and reduce cholesterol crystal formation and hence prevent cholesterol gallstone formation.
Animals ; Aspartate Aminotransferases ; blood ; Bile ; chemistry ; Cholesterol ; blood ; Gallbladder ; Gallstones ; metabolism ; prevention & control ; Liver ; metabolism ; pathology ; Male ; Malondialdehyde ; metabolism ; Mice ; Mice, Inbred C57BL ; Piper ; chemistry ; Plant Oils ; isolation & purification ; pharmacology ; Plants, Medicinal ; chemistry ; Random Allocation ; Superoxide Dismutase ; metabolism ; Triglycerides ; blood

OBJECTIVETo study the role of arginase-1 (Arg-1) expression in differential diagnosis of hepatocellular carcinoma (HCC), Arg-1 staining pattern in clear cell neoplasm (HCC and non-HCC) and Arg-1 expression in non-hepatocellular tumors.

METHODSSeventy-eight cases of HCC (including 8 cases of clear cell type and 70 cases of non- clear cell type) and 246 cases of non-hepatocellular neoplasms (including 29 cases of metastatic tumors such as breast cancer, nasopharyngeal carcinoma and neuroendocrine carcinoma, 77 cases of tumors with clear cell changes such as malignant melanoma, clear cell renal cell carcinoma and alveolar soft part sarcoma, and 140 cases of other types of tumors such as ovarian endometrioid adenocarcinoma, pituitary tumor and thyroid papillary carcinoma) were studied.Immunohistochemical study for Arg-1 was performed on the paraffin-embedded tumor tissue.

RESULTSIn HCC, Arg-1 demonstrated both cytoplasmic and nuclear staining, with an overall sensitivity of 96.2% (75/78).In well, moderately and poorly differentiated HCC, the sensitivity was 15/15, 100% (41/41) and 86.4% (19/22), respectively. That was in contrast to negative staining for Arg-1 in all the 29 cases of metastatic tumors studied. The sensitivity, specificity, positive predictive value and negative predictive value of Arg-1 in distinguishing HCC from metastatic tumors was 96.2%, 100%, 100% and 90.6%, respectively. Cytoplasmic and membranous staining was observed in clear cell type of HCC. The overall sensitivity of Arg-1 expression in the 77 cases of tumors with clear cell changes was 14.3% (11/77), including 8/15 for malignant melanoma, 2/4 for ovarian clear cell carcinoma and 1/1 gall bladder adenocarcinoma with clear cell component.In malignant melanoma and ovarian clear cell carcinoma, only cytoplasmic staining was demonstrated. There was no expression of Arg-1 in the 140 cases of other tumor types studied.

CONCLUSIONSArg-1 is a sensitive and specific marker for HCC.It is a potentially useful immunohistochemical marker in distinguishing HCC from metastatic tumors. Though also expressed in malignant melanoma and ovarian clear cell carcinoma, Arg-1 shows a different staining pattern as compared with that in HCC.

Adenocarcinoma ; enzymology ; Adult ; Aged ; Arginase ; metabolism ; Carcinoma, Hepatocellular ; enzymology ; pathology ; secondary ; Cell Differentiation ; Diagnosis, Differential ; Female ; Gallbladder Neoplasms ; enzymology ; Humans ; Liver Neoplasms ; enzymology ; pathology ; secondary ; Male ; Melanoma ; enzymology ; Middle Aged ; Ovarian Neoplasms ; enzymology ; Stomach Neoplasms ; enzymology ; pathology

BACKGROUND/AIMS: Few studies have assessed the prognostic value of the primary tumor maximum standardized uptake value (SUVmax) measured by 2-[18F]-fluoro-2-deoxy-D-glucose PET-CT for patients with bile duct and gallbladder cancer. METHODS: A retrospective analysis of 61 patients with confirmed bile duct and gallbladder cancer who underwent FDG PET-CT in Kangbuk Samsung Medical Center (Seoul, Korea) from April 2008 to April 2011. Prognostic significance of SUVmax and other clinicopathological variables was assessed. RESULTS: Twenty-three patients were diagnosed as common bile duct cancer, 17 as hilar bile duct cancer, 12 as intrahepatic bile duct cancer, and nine as gallbladder cancer. In univariate analysis, diagnosis of intrahepatic cholangiocarcinoma and gallbladder cancer, mass forming type, poorly differentiated cell type, nonsurgical treatment, advanced American Joint Committee on Cancer (AJCC) staging and primary tumor SUVmax were significant predictors of poor overall survival. In multivariate analysis adjusted for age and sex, primary tumor SUVmax (hazard ratio [HR], 4.526; 95% CI, 1.813-11.299), advanced AJCC staging (HR, 4.843; 95% CI, 1.760-13.328), and nonsurgical treatment (HR, 6.029; 95% CI, 1.989-18.271) were independently associated with poor overall survival. CONCLUSIONS: Primary tumor SUVmax measured by FDG PET-CT is an independent and significant prognostic factor for overall survival in bile duct and gallbladder cancer.
Aged ; Bile Duct Neoplasms/*diagnosis/mortality/radionuclide imaging ; Cholangiocarcinoma/diagnosis/mortality/radionuclide imaging ; Female ; Fluorodeoxyglucose F18/diagnostic use/metabolism/standards ; Gallbladder Neoplasms/*diagnosis/mortality/radionuclide imaging ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/diagnosis/mortality/radionuclide imaging ; Male ; Middle Aged ; Neoplasm Staging ; Positron-Emission Tomography/standards ; Prognosis ; Proportional Hazards Models ; Radiopharmaceuticals/diagnostic use/metabolism/standards ; Retrospective Studies ; Tomography, X-Ray Computed/standards

Animals ; Cholestasis ; complications ; Fibrosis ; etiology ; Gallbladder ; pathology ; Humans ; Kidney ; pathology ; Lipid Metabolism ; Liver Cirrhosis ; etiology ; therapy ; Myocardium ; pathology ; Receptors, Cytoplasmic and Nuclear ; physiology

OBJECTIVETo study the relationship between the change of coagulation and the clinicopathologic characteristics in patients with gallbladder cancer.

METHODSThe 64 gallbladder cancer patients (GBC group) and 60 cholecystitis patients (control group) had been reviewed from January 2007 to June 2013. The prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), and thrombin time (TT) had been measured and compared between patients of GBC group and control group. The relationship of coagulation function and prognosis were analyzed.

RESULTSCompared with control group, APTT in GBC group ((29.0 ± 4.2) s) was significantly shortened (t = -4.265, P = 0.000) and PT ((11.5 ± 1.4) s), TT ((15.3 ± 3.5) s), Fib ((4.1 ± 0.9) g/L) were significantly increased in GBC group (t = 2.521, 4.147 and 4.365, all P < 0.05). The level of Fib was higher in patients with medium or poor-differentiated tumor cells (F = 4.069, P = 0.022), lymph metastasis (t = 2.640, P = 0.010) and advanced staging (II-IV) (t = 3.003, P < 0.01) than those of well-differentiated, non-lymph metastasis and early staging (0-I). The ratio of gallbladder cancer with hyperfibrinogenemia (32/64) was significantly higher than control group (11/60, χ(2) = 13.709, P < 0.01). In GBC group, compared with normal Fib patients, hyperfibrinogenemia patients showed significantly difference in clinicopathologic characteristics (χ(2) = 5.851-10.573, P < 0.05). The average survival period of hyperfibrinogenemia patients and normal Fib patients were 8.63 months and 16.73 months. The 1-, 3-year survival rate of patients with hyperfibrinogenemia were significantly lower than those with normal Fib (64.7%, 14.9% vs. 74.9%, 21.1%, P < 0.05).

CONCLUSIONPreoperative plasma level of Fib might be a new promising biomarker in patients with gallbladder cancer for evaluating disease progression and prognosis.

Adult ; Aged ; Aged, 80 and over ; Blood Coagulation ; Case-Control Studies ; Female ; Fibrinogen ; metabolism ; Gallbladder Neoplasms ; physiopathology ; Humans ; Male ; Middle Aged ; Prognosis ; Prothrombin Time