Cholangiocarcinoma Metastasis Research Articles

Suppression of histone deacetylase 1 by JSL-1 attenuates the progression and metastasis of cholangiocarcinoma via the TPX2/Snail axis

Histone deacetylases (HDACs) are entwined with the pathogenesis of various cancers and potentially serve as promising therapeutic targets. Herein, we intend to explore the potential role of HDAC1 inhibitor (JSL-1) in the tumorigenesis and metastasis of cholangiocarcinoma (CC) and to highlight the molecular basis of its function. As shown by bioinformatics analysis and immunohistochemical detection, high HDAC1 expression was witnessed in CC tissues relative to matched controls from patients with cholecystitis. The molecular network that HDAC1 silencing reduced the enrichment of HDAC1 and Snail on the TPX2 promoter was identified using immunoprecipitation and chromatin immunoprecipitation assays. Both short hairpin RNA (shRNA)-mediated knockdown of HDAC1 and JSL-1 treatment exhibited anti-proliferative, anti-migration and anti-invasion effects on CC cells through downregulation of TPX2. The in vivo xenograft model was developed in nude mice. Consistently, the anti-tumorigenic and anti-metastatic properties of shRNA against HDAC1 and HDAC1 inhibitor were validated in the in vivo settings. Taken together, our data supported the notion that HDAC1 inhibitor retards the initiation and development of CC via mediating the TPX2/Snail axis, highlighting the anti-tumor molecular network functioned in CC.

Cholangiocarcinoma presenting as dysphagia and misdiagnosed as gastritis: a case report

BackgroundHeterotopic tumor is a rare disease. Thus far, no cases of heterotopic cholangiocarcinoma have been reported in the world. Cholangiocarcinoma mainly metastasizes by direct invasion, and it can lead to liver metastasis in its advanced stage. There were few clinical cases of gastric metastasis in advanced tumors, mainly seen in breast cancer, lung cancer, liver cancer, malignant melanoma, choriocarcinoma, and hematological tumors. Metastases of cholangiocarcinoma to the stomach also are exceptionally rare.Case presentationA 58-year-old man was admitted to the hospital because of difficulty swallowing for one year. Upon gastroscopy, we found the tumor at the region of the cardia and gastric fundus. Macroscopical appearance of the tumor suggested its malignant nature. Computed tomography (CT) findings showed that the wall of the cardia, fundus, and stomach body were thickened, suggesting a tumor. Because the patient had obvious difficulty swallowing, we invited cardiothoracic surgeons for consultation. They considered that the patient had definite mechanical obstruction in the lower esophagus; hence, they performed an operation. Immunohistochemical staining revealed low-to-medium differentiated adenocarcinoma (containing mucinous adenocarcinoma components) of biliary origin.ConclusionsWe highlight the importance of the endoscopic biopsy of gastric tumor. However, when its results are inconsistent with the clinician’s judgment, further examination is required. Endoscopic ultrasonography and enhanced CT may be a good choice. If necessary, on the premise of patient acceptance, the diagnosis could be confirmed after surgical excision. Here we report a case of a patient with heterotopic cholangiocarcinoma in the gastric fundus. The most common tissue ectopias in the digestive tract include esophagogastric gastric mucosal ectopia, duodenal gastric mucosal ectopia, and gastric mucosal small intestinal ectopia. Thus far, there have been no reports of ectopic cholangiocarcinoma and associated cancer in the stomach. In addition, metastases of cholangiocarcinoma to the stomach are also exceptionally rare, and most of them are due to a direct invasion. The discovery of the primary lesion is an important clue for the reliable diagnosis in such cases.

Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways.

Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 (B3GNT6) and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway.

Prognostic impact of the metastatic lymph node number in intrahepatic cholangiocarcinoma

BackgroundLymph node metastasis in intrahepatic cholangiocarcinoma is a poor prognostic factor after radical surgery. However, unlike other biliary tract malignancies, the nodal stage of intrahepatic cholangiocarcinoma only reflects the presence of metastatic lymph nodes, not the number of metastatic lymph nodes. This study aimed to identify the prognostic impact of the metastatic lymph node number in intrahepatic cholangiocarcinoma. MethodsThe data from 87 patients with intrahepatic cholangiocarcinoma who had undergone hepatectomy with 5 or more harvested lymph nodes and covering stations 12 and 8 based on the previous criteria from January 2006 to December 2019 were retrospectively reviewed. The hazard ratio according to the increasing metastatic lymph node number was calculated with other known prognostic factors for intrahepatic cholangiocarcinoma. The patients were then divided into 3 groups according to the metastatic lymph node number (N0 [n = 45]: no metastatic lymph nodes; N+ <4 [n = 32]: 1 to 3 metastatic lymph nodes; N+ ≥4 [n = 10]: ≥4 metastatic lymph nodes). Disease-free survival and overall survival were also analyzed. ResultsThe metastatic lymph node number was a prognostic factor of oncologic survival (disease-free survival: hazard ratio = 1.18 [1.05–1.32], P = .005; overall survival: hazard ratio = 1.21 [1.06–1.37], P = .004). Survival analysis revealed significantly poorer outcomes with an increasing metastatic lymph node number (disease-free survival: N0 vs N+ <4 vs N+ ≥4: 36.0 [0.0–76.0] vs 8.0 [0.0–16.9] vs 2.0 [0.0–5.1] months, P < .001; overall survival: N0 vs N+ <4 vs N+ ≥4: 69.0 [24.5–113.5] vs 28.0 [18.9–37.1] vs 11.0 [6.4–15.6] months, P < .001). In post hoc analysis, a significant difference was found between adjacent groups (disease-free survival and overall survival: N+ <4 vs N+ ≥4, P = .001). ConclusionWith proper lymph node dissection, the number of metastatic lymph nodes is a prognostic factor of intrahepatic cholangiocarcinoma.

CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma

BackgroundConsiderable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood.MethodscircNFIB (hsa_circ_0086376, termed as cNFIB hereafter) was identified in human ICC tissues through circRNAs sequencing. The biological role of cNFIB was determined in vitro and in vivo by gain or loss of functional experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to analyze the interaction of cNFIB with dual specificity mitogen-activated protein kinase kinase1 (MEK1). Duolink in situ proximity ligation assay (PLA) and coimmunoprecipitation (co-IP) assay were used to investigate the effects of cNFIB on the interaction between MEK1 and mitogen-activated protein kinase 2 (ERK2). Finally, a series of in vitro and in vivo experiments were performed to explore the influences of cNFIB on the anti-tumor activity of trametinib (a MEK inhibitor).ResultscNFIB was significantly down-regulated in human ICC tissues with postoperative metastases. The loss of cNFIB was highly associated with aggressive characteristics and predicted unfavorable prognosis in ICC patients. Functional studies revealed that cNFIB inhibited the proliferation and metastasis of ICC cells in vitro and in vivo. Mechanistically, cNFIB competitively interacted with MEK1, which induced the dissociation between MEK1 and ERK2, thereby resulting in the suppression of ERK signaling and tumor metastasis. Moreover, we found that ICC cells with high levels of cNFIB held the potential to delay the trametinib resistance. Consistently, in vivo and in vitro studies demonstrated that cotreatment with trametinib and lentivirus vector encoding cNFIB showed greater inhibitory effect than isolated trametinib treatment.ConclusionsOur findings identified that cNFIB played a key role in ICC growth and metastasis by regulating MEK1/ERK signaling. Given the efficacy of cNFIB modulation on ICC suppression and trametinib sensitivity, cNFIB appears to be a potential therapeutic molecule for ICC treatment.

Prognostic Impact of Metastatic Lymph Node Numbers for Intrahepatic Cholangiocarcinoma

Background: Lymph node (LN) metastasis in intrahepatic cholangiocarcinoma (ICC) is one of the poor prognostic factors after radical surgery. However, unlike other biliary tract malignancies, the nodal stage of ICC only reflects the presence of metastatic LN, not the number of metastatic LNs. This study aims to identify the prognostic impact of metastatic LN numbers in ICC. Methods: Data from 102 ICC patients who underwent hepatectomy with 5 or more harvested LNs and covering stations No. 12 and 8 from January 2006 to December 2019 were retrospectively reviewed. Hazard ratio (HR) according to increasing metastatic LN number was calculated with other known prognostic factors for ICC. Using the result, the patients were divided into 3 groups according to the number of metastatic LNs (N0 group (n=50): no metastatic LN, N+<4 groups (n=39): 1-3 metastatic LNs, N+≥4 group (n=13): ≥4 metastatic LNs) and disease-free survival (DFS) and overall survival (OS) were analyzed. Results: Metastatic LN numbers were prognostic factors of oncologic survival. (DFS; HR=1.18[1.06-1.30], p=0.002, OS; HR=1.22[1.09-1.37], p=0.001) In the survival analysis, significantly poor outcomes were shown with an increasing number of metastatic LNs. (DFS; N0 vs. N+<4 vs. N+≥4: 36.0[0.0-76.9] vs. 9.0[2.9-15.1] vs. 2.0[0.6-3.4] months, p>0.001, OS; N0 vs. N+<4 vs. N+≥4: 69.0[30.6-107.4] vs. 26.0[21.3-30.7] vs. 10.0[7.7-12.3] months, p>0.001) In the post hoc analysis, a significant difference between adjacent groups was shown. (DFS and OS; N+<4 vs. N+≥4: p<0.001). Conclusion: With proper LN dissection, the number of metastatic LNs is a prognostic factor of ICC.Tabled 1EP01C-061Disease-free survivalOverall survivalUnivariateMultivariateUnivariateMultivariateHR (95%CI)p-valueHR (95%CI)p-valueHR (95%CI)p-valueHR (95%CI)p-valueT stage0.2280.3450.3040.375T43.69 (0.91-14.93)0.0683.79 (0.89-16.18)0.0723.09 (0.76-12.52)0.1152.72 (0.63-11.84)0.182T32.72 (1.10-6.76)0.0312.23 (0.88-5.66)0.0922.64 (1.05-6.60)0.0382.29 (0.89-5.88)0.084T22.33 (0.97-5.62)0.0601.80 (0.73-4.46)0.2042.18 (0.90-5.32)0.0851.54 (0.61-3.89)0.360T1b1.93 (0.70-5.33)0.2041.61 (0.55-4.72)0.3901.86 (0.68-5.13)0.2301.40 (0.47-4.15)0.540T1a(Reference)(Reference)(Reference)(Reference)Metastatic LN1.25 (1.15-1.35)<0.0011.18 (1.06-1.30)0.0021.28 (1.17-1.40)<0.0011.22 (1.09-1.37)0.001 Open table in a new tab

Modification of STIM2 by m6A RNA methylation inhibits metastasis of cholangiocarcinoma.

BackgroundN6-methyladenosine (m6A) is the most frequent internal methylation of eukaryotic RNA (ribonucleic acid) transcripts and plays an important function in RNA processing. The current research aimed to investigate the role of m6A-STIM2 axis in cholangiocarcinoma (CCA) progression.MethodsThe expression of STIM2 (Stromal Interaction Molecule 2) in CCA was measured using quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC). STIM2 was examined in vivo for its effects on the malignant phenotypes of CCA cells. The m6A modification of STIM2 was assessed through MeRIP (methylated RNA Immunoprecipitation)-PCR.ResultsBased on the GEPIA (Gene Expression Profiling Interactive Analysis) 2 database findings, a low STIM2 mRNA (messenger RNA) level was related to a poor prognosis in individuals with CCA. Quantitative PCR and IHC assays indicated decreased protein satin in CCA tissues and were associated with extrahepatic metastasis. Vianude mice tail vein injection model indicated that increased STIM2 levels suppressed CCA cell metastasis in vivo, while KRT8 (keratin 8) was detected as the direct downstream target of STIM2-mediated CCA cell metastasis in vivo. Meanwhile, based on SRAMP database and MeRIP assays indicated that m6A alteration resulted in abnormal STIM2 expression in CCA via METTL14 and YTHDC2.ConclusionsOur findings revealed the epi-transcriptomic dysregulation in CCA and metastasis by proposing a complicated STIM2-KRT8 regulatory paradigm based on m6A alteration.

ACOT12-mediated acetyl-CoA hydrolysis suppresses intrahepatic cholangiocarcinoma metastasis by inhibiting epithelial-mesenchymal transition.

Intrahepatic cholangiocarcinoma (ICC) is the most common malignant bile duct tumor in the liver and the second most common primary liver cancer with increasing morbidity and poor prognosis. Metabolic aberration plays key roles in cancer progression. As a key metabolic intermediate, acetyl-CoA accumulation shows close association with cancer metastasis. However, the role of acetyl-CoA metabolic aberration in ICC is still undetermined. Here, by investigating tissue samples from ICC patients and ICC cell lines, we found that acyl-CoA thioesterase 12 (ACOT12) expression is significantly down-regulated in ICC tissues, and is associated with poor prognosis of ICC. In vitro and in vivo studies demonstrated that ACOT12 suppressed ICC cells metastasis. Further mechanistic studies revealed that down-regulation of ACOT12 promoted ICC metastasis by inducing Slug expression and epithelial-mesenchymal transition (EMT). Our findings link ACOT12-regulated-acetyl-coA metabolic aberration with ICC metastasis and imply that ACOT12 could be a prognostic marker and a potential therapeutic target for ICC metastasis.

IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma.

Background and AimsIL‐6–induced tumor progression has been well established through the induction of antiapoptotic and proliferative genes. However, whether other mechanisms such as IL‐6 regulation of circular RNAs (circRNAs) may also contribute to tumor development remains unknown.Approach and ResultsHigh‐throughput RNA sequencing was used to identify the differentially expressed circRNAs on IL‐6 stimulation in intrahepatic cholangiocarcinoma (ICC) cells. CircRNA GGNBP2 (derived from ggnbp2 gene, termed as cGGNBP2) was up‐regulated by IL‐6 treatment in a time and concentration‐dependent manner. The biogenesis of cGGNBP2 was regulated by RNA‐binding protein DEx‐H Box Helicase 9, which was also mediated by IL‐6 exposure. Mass spectrometry and western blotting identified a protein cGGNBP2‐184aa encoded by cGGNBP2. cGGNBP2‐184aa promoted ICC cell proliferation and metastasis in vitro and in vivo. Mechanistically, cGGNBP2‐184aa directly interacted with signal transducers and activators of transduction‐3 (STAT3), phosphorylated STAT3Tyr705, and played a positive regulatory role in modulating IL‐6/STAT3 signaling. IL‐6/cGGNBP2‐184aa/STAT3 formed a positive feedback loop to sustain constitutive activation of IL‐6/STAT3 signaling. Elevated cGGNBP2 expression was correlated with poor prognosis of patients with ICC and was identified as an independent risk factor for patient prognosis.ConclusionsOur study demonstrates that cGGNBP2‐184aa, a protein encoded by IL‐6–induced cGGNBP2, formed a positive feedback loop to facilitate ICC progression and may serve as an auxiliary target for clinical IL‐6/STAT3‐targeting treatments in ICC.

Long non-coding RNA titin-antisense RNA1 contributes to growth and metastasis of cholangiocarcinoma by suppressing microRNA-513a-5p to upregulate stratifin

ABSTRACT Cholangiocarcinoma (CCA) is one of the most common histological types of primary hepatic malignancy and is associated with poor overall prognosis, causing a ponderous burden on human life. Hence, it is necessary to elucidate the pathogenesis of CCA. The objective of our research was to shed light on the mechanism through which long non-coding RNA titin-antisense RNA1 (lncRNA TTN-AS1) is involved in the development of CCA. Reverse transcription quantitative polymerase chain reaction was used to detect TTN-AS1 expression in CCA samples and cells. Functional experiments were performed using the Cell Counting Kit-8, 5-ethynyl-2ʹ-deoxyuridine, transwell, and in vivo tumor growth assays. The relationship between TTN-AS1, miR-513a-5p, and stratifin (SFN) was explored using a dual luciferase reporter assay, RNA immunoprecipitation (RIP) experiment, and Pearson correlation analysis. The result showed that TTN-AS1 and SFN are highly expressed in CCA tissues. Bioinformatics analysis, luciferase reporter and RIP experiments revealed the correlation between TTN-AS1, miR-513a-5p, and SFN. In addition, silencing TTN-AS1 mitigated CCA cell proliferation and migration. Mechanistically, miR-513a-5p is sponged by TTN-AS1. The miR-513a-5p inhibitor abolished the effect of TTN-AS1 silencing on the aggressive behaviors of CCA cells. Furthermore, we showed that miR-513a-5p is a regulator of CCA by targeting SFN. TTN-AS1 induced CCA cell growth and metastasis via the miR-513a-5p/SFN pathway, which offers a new strategy for therapeutic interventions for CCA.

Machine learning-based Radiomics analysis for differentiation degree and lymphatic node metastasis of extrahepatic cholangiocarcinoma

BackgroundRadiomics may provide more objective and accurate predictions for extrahepatic cholangiocarcinoma (ECC). In this study, we developed radiomics models based on magnetic resonance imaging (MRI) and machine learning to preoperatively predict differentiation degree (DD) and lymph node metastasis (LNM) of ECC.MethodsA group of 100 patients diagnosed with ECC was included. The ECC status of all patients was confirmed by pathology. A total of 1200 radiomics features were extracted from axial T1 weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), and apparent diffusion coefficient (ADC) images. A systematical framework considering combinations of five feature selection methods and ten machine learning classification algorithms (classifiers) was developed and investigated. The predictive capabilities for DD and LNM were evaluated in terms of area under precision recall curve (AUPRC), area under the receiver operating characteristic (ROC) curve (AUC), negative predictive value (NPV), accuracy (ACC), sensitivity, and specificity. The prediction performance among models was statistically compared using DeLong test.ResultsFor DD prediction, the feature selection method joint mutual information (JMI) and Bagging Classifier achieved the best performance (AUPRC = 0.65, AUC = 0.90 (95% CI 0.75–1.00), ACC = 0.85 (95% CI 0.69–1.00), sensitivity = 0.75 (95% CI 0.30–0.95), and specificity = 0.88 (95% CI 0.64–0.97)), and the radiomics signature was composed of 5 selected features. For LNM prediction, the feature selection method minimum redundancy maximum relevance and classifier eXtreme Gradient Boosting achieved the best performance (AUPRC = 0.95, AUC = 0.98 (95% CI 0.94–1.00), ACC = 0.90 (95% CI 0.77–1.00), sensitivity = 0.75 (95% CI 0.30–0.95), and specificity = 0.94 (95% CI 0.72–0.99)), and the radiomics signature was composed of 30 selected features. However, these two chosen models were not significantly different to other models of higher AUC values in DeLong test, though they were significantly different to most of all models.ConclusionMRI radiomics analysis based on machine learning demonstrated good predictive accuracies for DD and LNM of ECC. This shed new light on the noninvasive diagnosis of ECC.

Proteomic analysis of serum and serum exosomes, and their application in intrahepatic cholangiocarcinoma

外泌体是由各种类型细胞在正常或非正常生理情况下分泌释放至细胞外且携带多种生物活性分子的细胞外囊泡,在细胞间通讯和免疫应答等生物过程中发挥着重要作用。肝内胆管癌是一种胆道上皮恶性肿瘤,早期无明显临床症状且生存率较低,目前常用的诊断手段包括依赖于影像设备的诊断方式和灵敏度及特异性较低的诊断标志物等,这些手段的不足对发展新的特异性标志物提出了需求。该文对血清中的外泌体进行了分离和表征,并采用液相色谱-质谱技术针对健康组与肝内胆管癌患者组的血清样本和血清外泌体样本进行了无标记定量蛋白质组学分析,分别从两种类型样本中鉴定并筛选到271和430种可信蛋白质。基于血清样本和血清外泌体样本的可信蛋白质定量表达值进行多维统计分析都能将健康组与肝内胆管癌患者组良好地区分开。对血清样本中鉴定到的蛋白质进行差异蛋白质筛选,肝内胆管癌患者组相对于健康组有15个上调和8个下调蛋白质;对血清外泌体样本中鉴定到的蛋白质进行差异蛋白质筛选,肝内胆管癌患者组相对于健康组有33个上调和18个下调蛋白质;基于两种样本筛选到的差异蛋白质中仅有4个是重复的,且基于血清外泌体样本的51个差异蛋白质中有35个蛋白质属于外泌体蛋白质数据库。针对差异蛋白质进行生物学信息分析,与差异蛋白质相关的分子功能、生物过程和信号通路主要涉及天然免疫反应、炎症反应和凝血等过程。该研究为发现肝内胆管癌的潜在生物标志物和探究肝内胆管癌的发生、发展和转移等过程提供了参考和借鉴价值。此外,通过比较研究发现血清外泌体样本能够获得较多的差异蛋白质和生物学信息,证明了外泌体作为组学分析样本的价值和应用潜力。

The LIN28B/TGF-β/TGFBI feedback loop promotes cell migration and tumour initiation potential in cholangiocarcinoma

Cholangiocarcinoma (CCA), a lethal malignancy of the biliary epithelium, is the second most common primary liver cancer. The poor prognosis of CCA is due to the high rate of tumour invasion and distant metastasis. We found that the RNA-binding protein LIN28B, a known regulator of microRNA biogenesis, stem cell maintenance, and oncogenesis, is expressed in a subpopulation of CCA patients. To further investigate the potential role of LIN28B in CCA pathogenesis, we studied the effect of LIN28B overexpression in the cholangiocyte cell line MMNK-1 and cholangiocarcinoma cell lines HuCCT-1 and KKU-214. Here, we show that enhanced LIN28B expression promoted cancer stem cell-like properties in CCA, including enhanced cell migration, epithelial-to-mesenchymal transition (EMT), increased cell proliferation and spheroid formation. Proteomic analysis revealed TGF-β-induced protein (TGFBI) as a novel LIN28B target gene, and further analysis showed upregulation of other components of the TGF-β signalling pathway, including TGF-β receptor type I (TGFBRI) expression and cytokine TGFB-I, II and III secretion. Importantly, the small molecule TGF-β inhibitor SB431542 negated the effects of LIN28B on both cell migration and clonogenic potential. Overexpression of TGFBI alone promoted cholangiocarcinoma cell migration and EMT changes, but not spheroid formation, suggesting that TGFBI partially contributes to LIN28B-mediated aggressive cell behaviour. These observations are consistent with a model in which TGF-β and LIN28B work together to form a positive feedback loop during cholangiocarcinoma metastasis and provide a therapeutic intervention opportunity.

Prediction and treatment of lymph node metastasis of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second largest primary liver cancer, and lymph node metastasis of ICC is commonly observed. Lymph node metastasis not only affects the prognosis of patients, but also determines the choice of treatment regimen. This article summarizes related articles on ICC in China and globally and elaborates on the serological markers and imaging indicators for predicting lymph node metastasis of ICC, the controversy over the selection of lymph node resection and postoperative adjuvant treatment for patients eligible for radical resection, and the research advances in neoadjuvant therapy for patients with advanced ICC who cannot undergo surgery, so as to provide theoretical support for the treatment of ICC patients and the prediction of lymph node metastasis.

MicroRNA-7-5p Inhibits Migration, Invasion and Metastasis of Intrahepatic Cholangiocarcinoma by Inhibiting MyD88.

Background and AimsIntrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from intrahepatic bile duct epithelial cells. Accumulating studies report that microRNAs are widely involved in tumor migration and metastasis by regulation of target genes. miR-7-5p has been confirmed to inhibit tumor metastasis and to be related to prognosis for several malignant tumors. Our study investigated the underlying functions of miR-7-5p in ICC.MethodsThe expression of miR-7-5p in ICC tissues but also in ICC cell lines was analyzed by real-time PCR. By analyzing the relationship between the clinicopathological parameters of 60 ICC patients and the expression level of miR-7-5p, the effect of miR-7-5p on the prognosis was clarified. After transfected with miR-7-5p mimics or miR-7-5p inhibitor, cell counting kit-8 assay was applied to evaluate the cells proliferation, flow cytometry was applied to analyze the cells apoptosis, wound healing assay and transwell chamber assay were applied to analyze the cell invasion and migration. A luciferase reporter assay was identified the relationship of miR-7-5p and myeloid differentiation factor 88 (MyD88). Western blotting was used to analyze the proteins expression. And immunochemistry was performed to determine the expression of MYD88 in ICC tissues.ResultsOur data showed the expression of miR-7-5p was down-regulated not only in ICC tissues but also in ICC cell lines compared with normal controls. Low expression of miR-7-5p was notably associated with poor prognosis in ICC patients. miR-7-5p negatively regulated cell proliferation, migration, invasion and apoptosis in ICC cells. We further verified that MyD88 was a novel target of miR-7-5p and was significantly overexpressed in ICC tissues. Overexpression of MyD88 counteracted the effects of miR-7-5p in ICC cells.ConclusionsThe present findings suggest that miR-7-5p plays a pivotal role in ICC invasion by regulating MyD88. Ampliative insight into the key factors of ICC invasion may result in the development of new treatment options for ICC.

Overexpression of Capns1 Predicts Poor Prognosis and Correlates with Tumor Progression in Renal Cell Carcinoma

Introduction: Calpain small subunit 1 (Capns1) has shown its correlation with the metastasis and invasion of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, the expression and function of Capns1 in human renal cell carcinoma (RCC) have not been clarified. This study aimed to examine the expression of Capns1 in RCC tissues and cell lines and to assess its role performed in RCC. Methods: Capns1 expression was evaluated in 75 pairs of RCC and matched adjacent non-tumor tissues by immunohistochemistry. The prognostic value of Capns1 in RCC was assessed by Kaplan-Meier and Cox regression analyses. The action of Capns1 in the proliferation, adhesion, migration, and invasion of RCC cells and the effects on matrix metalloproteinase (MMP) 2 and 9 expression were evaluated after Capns1 silence. Results: Capns1 expression was significantly higher in RCC tissues compared with the adjacent non-tumor tissues. Multivariate analysis showed that Capns1 overexpression was an independent poor prognostic marker in RCC. The silencing of Capns1 prohibited cell adhesion and impaired the migration and invasion ability of 786-O cells in vitro. Furthermore, Capns1 silence reduced MMP2 and MMP9 expression. Conclusion: Capns1 overexpression predicts poor prognosis and correlates with tumor progression in RCC. Capns1 expression might serve a prognostic marker and therapeutic target for RCC.

Laparoscopic left hepatectomy for a patient with intrahepatic cholangiocarcinoma metastasis in the falciform ligament: a case report

BackgroundIntrahepatic cholangiocarcinoma (ICC) is primary cancer of the liver with poor prognosis because of its high potential for recurrence and metastasis. We experienced a rare case of ICC with hematogenous metastasis to the falciform ligament. We aimed to clarify the route of metastasis to the mesentery by increasing the accuracy of preoperative imaging and establish a hepatectomy to control cancer.Case presentation An 85-year-old woman was referred to our hospital for a detailed study of progressively increasing liver tumors. She had no subjective symptoms. Her medical history showed hypertension, aneurysm clipping for cerebral hemorrhage, and gallstones. A detailed physical examination and laboratory data evaluation included tumor markers but did not demonstrate any abnormalities. On computed tomography scan, contrast-enhanced ultrasound, and magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid, the tumor appeared to be located in liver segment IV, protruding outside the liver. It appeared to contain two distinct components; we suspected ICC in the intrahepatic tumor component. Laparoscopic observation revealed that the extrahepatic lesion was an intra-falciform ligament mass; laparoscopic left hepatectomy was performed. Microscopically, the main tumor in segment IV was 15 mm in diameter and was diagnosed as moderately and poorly differentiated ICC. The tumor of the intra-falciform ligament was not continuous with the main intrahepatic nodule and was also diagnosed as ICC with extensive necrosis. There were no infiltrates in the round ligament of the liver, and several tumor thrombi were found in the small veins of the falciform ligament.ConclusionsTo date, there have been a few reports of metastases of primary liver cancer to the falciform ligament. At the time of preoperative imaging and pathological diagnosis, this case was suggestive of considering that the malignant liver tumor might be suspected of metastasizing to the falciform ligament. Our case improves awareness of this pathology, which can be useful in the future when encountered by hepatic specialists and surgeons.

Circ-LAMP1 contributes to the growth and metastasis of cholangiocarcinoma via miR-556-5p and miR-567 mediated YY1 activation.

Dysregulation of circular RNAs (circRNAs) executes important regulatory roles in carcinogenesis. Nonetheless, few studies focused on the mechanisms of circRNAs in cholangiocarcinoma (CCA). qRT‐PCR was applied to verify the dysregulated circRNAs in CCA. Fisher's exact test, Kaplan‐Meier analysis and Cox regression model were utilized to investigate the clinical implications of circ‐LAMP1 in the patients with CCA. The viability, apoptosis, migration and invasion of CCA cells were detected after silencing/overexpression of circ‐LAMP1. Xenograft and lung metastasis assays were performed to verify the in vitro results. The regulatory networks of circ‐LAMP1 were unveiled by bioinformatic analysis, RNA immunoprecipitation (RIP), RNA pulldown and luciferase reporter assays. Up‐regulation of circ‐LAMP1 was found in CCA tissue samples and cell lines. Enhanced level of circ‐LAMP1 was linked to clinical severity, high post‐operative recurrence and poor prognosis for the patients with CCA. Gain/loss‐of‐function assays confirmed the oncogenic role of circ‐LAMP1 in mediating cell growth, apoptosis, migration and invasion. Nevertheless, the level of circ‐LAMP1 had no effect on normal biliary epithelium proliferation and apoptosis. Animal study further verified the in vitro data. Mechanistically, circ‐LAMP1 directly sponged miR‐556‐5p and miR‐567, thereby releasing their suppression on YY1 at post‐transcriptional level. Rescue assay indicated that the oncogenic role of circ‐LAMP1 is partially dependent on its modulation of YY1 in CCA. In summary, this study suggested that circ‐LAMP1 might be used as a promising biomarker/therapeutic target for CCA.

Role of miRNA in the development and progression of cholangiocarcinoma

Cholangiocarcinoma is the most common malignant tumor of the biliary tract, with a relatively high mortality rate and an incidence rate increasing year by year. Due to atypical symptoms in the early stage and complex anatomical location, it is often difficult for patients with cholangiocarcinoma to be diagnosed in the early stage, and therefore, they often miss the optimal treatment period and tend to have poor prognosis. In recent years, studies have shown that miRNAs play a key role in the pathophysiological process of the development and progression of cholangiocarcinoma. This article reviews the regulatory role of miRNAs in the development, invasion, metastasis, drug resistance, and tumor microenvironment of cholangiocarcinoma and introduces the latest advances in exosome miRNA and cholangiocarcinoma, so as to provide potential treatment strategies for cholangiocarcinoma.

A Novel Approach to Assessing Differentiation Degree and Lymph Node Metastasis of Extrahepatic Cholangiocarcinoma: Prediction Using a Radiomics-Based Particle Swarm Optimization and Support Vector Machine Model.

BackgroundRadiomics can improve the accuracy of traditional image diagnosis to evaluate extrahepatic cholangiocarcinoma (ECC); however, this is limited by variations across radiologists, subjective evaluation, and restricted data. A radiomics-based particle swarm optimization and support vector machine (PSO-SVM) model may provide a more accurate auxiliary diagnosis for assessing differentiation degree (DD) and lymph node metastasis (LNM) of ECC.ObjectiveThe objective of our study is to develop a PSO-SVM radiomics model for predicting DD and LNM of ECC.MethodsFor this retrospective study, the magnetic resonance imaging (MRI) data of 110 patients with ECC who were diagnosed from January 2011 to October 2019 were used to construct a radiomics prediction model. Radiomics features were extracted from T1-precontrast weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion-weighted imaging (DWI) using MaZda software (version 4.6; Institute of Electronics, Technical University of Lodz). We performed dimension reduction to obtain 30 optimal features of each sequence, respectively. A PSO-SVM radiomics model was developed to predict DD and LNM of ECC by incorporating radiomics features and apparent diffusion coefficient (ADC) values. We randomly divided the 110 cases into a training group (88/110, 80%) and a testing group (22/110, 20%). The performance of the model was evaluated by analyzing the area under the receiver operating characteristic curve (AUC).ResultsA radiomics model based on PSO-SVM was developed by using 110 patients with ECC. This model produced average AUCs of 0.8905 and 0.8461, respectively, for DD in the training and testing groups of patients with ECC. The average AUCs of the LNM in the training and testing groups of patients with ECC were 0.9036 and 0.8889, respectively. For the 110 patients, this model has high predictive performance. The average accuracy values of the training group and testing group for DD of ECC were 82.6% and 80.9%, respectively; the average accuracy values of the training group and testing group for LNM of ECC were 83.6% and 81.2%, respectively.ConclusionsThe MRI-based PSO-SVM radiomics model might be useful for auxiliary clinical diagnosis and decision-making, which has a good potential for clinical application for DD and LNM of ECC.