Exceptional metal-semiconductor-metal transition of lead apatites via oxygen defect tuning.

Lead apatites, distinguished and compelling bulk materials with the stoichiometric arrangement as Pb10(POx)6Oy, are renowned for their structural complexity. Recently, the discovery of possible room-temperature superconductivity under ambient pressure in copper-substituted lead apatites has engendered considerable interest within both the physics community and beyond. Nevertheless, exploration of pristine Pb10(POx)6Oy parent structures has hitherto remained elusive. In this study, we employ density functional theory (DFT) calculations to investigate the effects of oxygen defects on the electronic structures of Pb10(POx)6Oy and Pb9Cu(POx)6Oy. We scrutinize two distinct categories of defects: oxygen atoms enmeshed within POx groups (Ox) and solitary oxygen atoms (Oy). Our investigation uncovers a profound influence of these defects on the band structure. Specifically, the introduction of Oy defects prompts a remarkable transition in Pb10(PO4)6Oy from a metal to semiconductor to metal state, accompanied by pivotal shifts in the principal electronic contributors from p orbitals of Oy to those of Pb atoms. Furthermore, the introduction of Ox defects in Pb10(POx)6O1 engenders metamorphosis in the band structure, transmuting it from a semiconductor to a metallic state. Significantly, our findings pinpoint the suitable range of x in the Pb10(POx)6O1 configuration as lying between 2 and 4. Additionally, our study also demonstrates that the oxygen defects (Ox/Oy) do not affect the metallic properties of copper-substituted lead apatites. This study elucidates the significant role of oxygen defects in modulating the electronic properties of apatite materials, offering insights into potential interdisciplinary applications. This establishes a crucial link between material composition and electronic behavior, revealing key mechanisms for engineering functionality in lead apatites and other advanced materials.

PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer.

BACKGROUND: Aberrant epigenetic remodeling events contribute to progression and metastasis of breast cancer (Bca). The specific mechanims that epigenetic factors rely on to mediate tumor aggressiveness remain unclear. We aimed to elucidate the roles of epigenetic protein PHF6 in breast tumorigenesis. METHODS: Published datasets and tissue samples with PHF6 staining were used to investigate the clinical relevance of PHF6 in Bca. CCK-8, clony formation assays were used to assess cell growth capacity. Cell migration and invasion abilities were measured by Transwell assay. The gene mRNA and protein levels were measured by quantitative real-time PCR and western blot. Chromatin immunoprecipitation (ChIP)-qPCR assays were used to investigate transcriptional relationships among genes. The Co-immunoprecipitation (Co-IP) assay was used to validate interactions between proteins. The CRISPR/Cas9 editing technology was used to construct double HIF knockout (HIF-DKO) cells. The subcutaneous xenograft model and orthotopic implantation tumor model were used to asess in vivo tumor growth. RESULTS: In this study, we utilized MTT assay to screen that PHF6 is required for Bca growth. PHF6 promotes Bca proliferation and migration. By analyzing The Cancer Genome Atlas breast cancer (TCGA-Bca) cohort, we found that PHF6 was significantly higher in tumor versus normal tissues. Mechanistically, PHF6 physically interacts with HIF-1α and HIF-2α to potentiate HIF-driven transcriptional events to initiate breast tumorigenesis. HIF-DKO abolished PHF6-mediated breast tumor growth, and PHF6 deficiency in turn impaired HIF transcriptional effects. Besides, hypoxia could also rely on YAP activation, but not HIF, to sustain PHF6 expressions in Bca cells. In addition, PHF6 recuits BPTF to mediate epigenetic remodeling to augment HIF transcriptional activity. Targeting PHF6 or BPTF inhibitor (AU1) is effective in mice models. Lastly, PHF6 correlated with HIF target gene expression in human breast tumors, which is an independent prognostic regulator. CONCLUSIONS: Collectively, this study identified PHF6 as a prognostic epigenetic regulator for Bca, functioning as a HIF coactivator. The fundamental mechanisms underlying YAP/PHF6/HIF axis in breast tumors endowed novel epigenegtic targets for Bca treatment.

Inhibition of 14-3-3ε by K50 acetylation activates YAP1 to promote cholangiocarcinoma growth.

14-3-3 proteins are ubiquitous adapters combining with phosphorylated serine/threonine motifs to regulate multiple cellular processes. As a negative regulator, 14-3-3 proteins could sequester the phosphorylated YAP1 in cytoplasm to inhibit its activity. In this study, we identified the K50 acetylation (K50ac) of 14-3-3ε protein and investigated its roles and mechanism in cholangiocarcinoma progression. The NAD (+)-dependent protein deacetylases inhibitor, NAM treatment significantly up-regulated the K50ac of 14-3-3ε. K50R mutation resulted in the decrease of K50ac of 14-3-3ε. The K50ac of 14-3-3ε was reversibly mediated by PCAF acetyltransferase and sirt1 deacetylases. K50ac had no obvious effect on the protein stability of 14-3-3ε, but inhibited the combination of 14-3-3ε with phosphorylated YAP1, which resulted in the activation of YAP1 in cholangiocarcinoma. K50R significantly decreased cholangiocarcinoma cell proliferation in vitro and the growth of tumor xenograft in vivo compared with WT (wild type) 14-3-3ε. The level of K50ac were higher in cholangiocarcinoma tissues accompanied by the accumulation of YAP1 in nuclear than para-carcinoma tissues. Our study revealed the underlying mechanism of K50ac of 14-3-3ε and its roles in cholangiocarcinoma, providing a potential targeting for cholangiocarcinoma therapy.

KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H 2S axis and contributes to pancreatic cancer growth.

In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (‒47/‒39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.

The clinical and prognostic factors for biliary neuroendocrine neoplasm: a study based on the SEER database.

BACKGROUND: In this study, we aimed at elucidating the postoperative survival and prognostic factors in patients with biliary neuroendocrine neoplasm (NEN). METHODS: Cases of biliary system NEN and adenocarcinoma from 1975 to 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A propensity score matching (PSM) method was used to adjust baseline differences in clinicopathological characteristics in our analysis. The Kaplan-Meier analysis was carried out for survival analysis. RESULTS: A total of 233 patients with biliary system NEN were enrolled in this study, of which 119 patients' lesions located in gallbladder, while the others' located in bile duct. The postoperative overall survival of bile duct NEN is significantly longer than that of gallbladder NEN (P < 0.001). For gallbladder NENs, surgery method (P = 0.020) and lymph node metastasis (P = 0.018) were identified as independent prognostic factors. In terms of ampulla of vater (AOV) NENs, age (P = 0.017) and lymph node metastasis (P = 0.006) were identified as independent prognostic factors, while grade (P = 0.002) and lymph node metastasis (P = 0.036) were identified as independent prognostic factors for extrahepatic bile duct (EBD) NENs. PSM analysis indicated that patients with biliary duct NENs have a better postoperative prognosis than biliary duct adenocarcinoma. CONCLUSIONS: Patients with NEN have better overall survival than patients with adenocarcinoma. Gallbladder NEN has an adverse prognosis than that of biliary tract NEN. The pathological subtype, differentiation, lymph node metastasis, surgery method, and lymph node resection could affect the postoperative prognosis of the gallbladder and biliary tract NEN.

Clinical correlation of cadherin-17 marker with advanced tumor stages and poor prognosis of cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.

MUC16 C-terminal binding with ALDOC disrupts the ability of ALDOC to sense glucose and promotes gallbladder carcinoma growth.

The MUC16 C-terminal (MUC16c) level is associated with tumor serum CA-125 levels, however, the roles remain unclear in gallbladder carcinoma (GBC). In this study, we found that MUC16c promoted glucose uptake and glycolysis for GBC cell proliferation. Mass spectrometry analysis suggested that MUC16c could combine with aldolase. The ALDOC mRNA and protein are overexpressed in GBC tumors. The IHC results also showed the consistent up-regulation of. ALDOC and MUC16c level in GBC tumor tissues than in peritumor tissues. We determined that MUC16c combining with ALDOC promoted ALDOC protein stability and disrupted the ability of ALDOC sensing glucose deficiency, which activated AMPK pathway and increased GBC cell proliferation. ALDOC knockdown significantly inhibited the glucose uptake and glycolysis induced by MUC16c. Our study established important roles of MUC16c promoting GBC cell glycolysis and proliferation and revealed the underlying mechanism of CA-125-related heavy tumor metabolic burden in GBC.

Serum lipid levels are the risk factors of gallbladder stones: a population-based study in China.

BACKGROUND: Gallstones are the cause of a majority of biliary tract discomfort. Although many community-based studies have addressed the risk factors for gallstone disease (GSD), little is known about GSD prevalence and risk factors in Chinese populations. METHODS: From January 2014 to January 2015, participants (N = 2,068,523) were recruited by Meinian Onehealth Healthcare Co., Ltd. They received a physical examination, and GSD was determined by ultrasound. RESULTS: The prevalence of GSD was 8.1%. Risks of GSD were similar between males and females in all age groups. Risk factors for gallstones include body mass index, waist circumference, waist-to-hip ratio, and physical activity, as well as biological factors such as age, sex, and elevated blood lipid levels. Serum lipid levels of GSD were statistically different from controls in total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (H-DL), low-density lipoprotein cholesterol (LDL), and apolipoprotein B (APOB). Furthermore, TC > 5.00 mmol/L, TG > 1.39 mmol/L, HDL < 1.19 mmol/L, LDL > 3.04 mmol/L, and APOB > 0.97 mmol/L were risk factors for gallstones. CONCLUSIONS: Serum lipid levels are associated with GSD. TC, TG, LDL, and APOB are risk factors, while HDL is a protective factor.

Downregulation of miR-106b induced breast cancer cell invasion and motility in association with overexpression of matrix metalloproteinase 2.

Breast cancer (BC) is one of the most common cancers in women, and it can often metastasize to the bone. The mechanism of BC bone metastasis remains unclear and requires in-depth investigation. In a previous study, we found the expression of matrix metalloproteinase 2 (MMP2) to be significantly more pronounced at metastatic bone sites than at orthotopic sites. MicroRNA expression profiling showed miR-106b to be markedly downregulated during BC bone metastasis. However, the specific manner in which MMP2 and miR-106b are involved in the BC bone metastasis is still unclear. In the present study, we found MMP2 expression in orthotopic tumor tissue to be related to the risk of bone metastasis in BC patients. MiR-106b levels in orthotopic tumor tissue showed a negative correlation with MMP2 expression and breast cancer bone metastasis. MMP2 was shown to be a direct target of miR-106b. Both gain- and loss-of-function studies showed that MMP2 could promote the migration and invasion of BC cells and that miR-106b could suppress both. The blockage of MMP2 by RNA interference mimicked the anti-migration and anti-invasion effects of miR-106b, and introduction of MMP2 antagonized the function of miR-106b. MMP2 was also found to regulate the ERK signaling cascade and so adjust the bone microenvironment to favor osteoclastogenesis and bone metastasis. These results suggest that MMP2 upregulation plays an important role in BC bone metastasis through ERK pathways, and miR-106b directly regulates MMP2 expression. The miR-106b/MMP2/ERK pathway may be a promising therapeutic target for inhibiting BC bone metastasis.

Exosomal microRNAs in hepatocellular carcinoma, expanding research field.

In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.

Liver and bile duct organoids and tumoroids.

Organoids refer to 3D cultures established to recapitulate histology, pathology, architecture, and genetic traits of various organs and tissues in the body, thereby replacing 2D cell cultures, xenograft, and animal models. Organoids form a 3D in vitro mimic of original tissues like the liver and are derived from embryonic or adult tissue stem cells. Liver and bile duct tumor organoids, also called, tumoroids capture genetic diversity, cellular, and pathophysiological properties of original tumors. Moreover, co-culture techniques along with genetic modulation of organoids allow for using tumoroids in liver and bile duct cancer research and drug screening/testing. Therefore, tumoroids are promising platforms for studying liver and bile duct cancer, which paves the way for the new era of personalized therapies. In the current review, we aimed to discuss liver and bile duct organoids with special emphasis on tumoroids and their applications, advantages, and shortcomings.

Low expression of RACK1 is associated with metastasis and worse prognosis in cholangiocarcinoma.

Background: Cholangiocarcinoma is a poorly prognostic malignant tumor, and the metastatic stage of cancer is not an early stage when diagnosed. Lymph node metastasis is common in the early stage. Ribosomal receptor for activated C-kinase 1 (RACK1) has found involved in the oncogenesis of various tumors and in the epithelial-mesenchymal transition (EMT). Nevertheless, its role in cholangiocarcinoma remains unknown. Material and methods: The possible correlation between RACK1 and tumor prognosis was analyzed in cholangiocarcinoma patients. The GEO and TCGA databases were used to evaluate the level of RACK1 in cholangiocarcinoma. The RBE and HCCC-9810 cell lines were used to examine the effects of RACK1 in the behavior of tumor cells in vitro. Results: The Kaplan-Meier analysis indicated that low expression of RACK1 was associated with poor prognosis and RACK1 was negatively related to lymph node metastasis, which were verified in databases TCGA and GEO; downregulation of RACK1 via RNA interference correlated with changes in the expression of EMT biomarkers and promoted the migration of cholangiocarcinoma cell lines. Conclusion: The protein expression of RACK1 is significantly higher in cholangiocarcinoma tissues than in peritumoral tissues, however, the high RACK1 expression indicates better overall survival and less risk for lymph node metastasis. In vitro, RACK1 may suppress the migratory ability of cholangiocarcinoma cells by inhibiting EMT.

Meta-analysis on the association between non-steroidal anti-inflammatory drug use and ovarian cancer.

AIM: Animal and in vitro studies suggest that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with reduced risk for ovarian cancer. However, results from these studies have been inconsistent. The aim of our study was to review and summarize the evidence provided by longitudinal studies on the association between NSAID use and ovarian cancer risk. METHODS: A comprehensive literature search for articles published up to December 2011 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risk (RR) or odds ratios (OR) were calculated. RESULTS: Seventeen reports (13 case-control studies, one clinical trial and three cohort studies), published between 1998 and 2011 were identified. There was no evidence of an association between aspirin use and ovarian cancer risk based on a random-effects model (RR = 0.91, 95% confidence interval (CI) 0.82, 1.01) or a fixed-effects model (RR = 0.94, 95% CI 0.87, 1.01). Similarly, we did not find strong evidence of an association between non-aspirin NSAID use and ovarian cancer using a random-effects model (RR = 0.89, 95% CI 0.74, 1.08) or a fixed-effects model (RR = 0.86, 95% CI 0.76, 0.98). Furthermore, our analysis did not show a strong association between frequency or duration of non-aspirin-NSAID use and ovarian cancer. CONCLUSIONS: Our findings indicate that there is no strong evidence of an association between aspirin/NA-NSAID use and ovarian cancer. However, this subject deserves further investigation.

Exposure to bisphosphonates and risk of colorectal cancer.

Animal and in vitro studies suggest that the use of bisphosphonates (BPs) may be associated with reduced risk for colorectal cancer (CRC). However, results from these studies have been inconsistent. The aim of our study was to review and summarize the evidence provided by longitudinal studies on the association between BP use and CRC risk A comprehensive literature search for articles published up to October 2012 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risks (RRs) or odds ratios were calculated. Six reports (four case-control studies and two cohort studies) published between 2010 and 2012 were identified. There was evidence of an association between any use of BPs and CRC risk using a fixed-effects model (RR = 0.80, 95% confidence interval = 0.74, 0.85) and a random-effects model (RR = 0.80, 95% confidence interval = 0.71, 0.90). However, we did not observe any evidence of a trend with increasing duration of use. Our findings indicate that there is evidence of an association between any use of BP and reduced CRC risk. However, this subject deserves further investigation.

Gene-based cancer-testis antigens as prognostic indicators in hepatocellular carcinoma.

Cancer/testis antigens (CTAs) are reproductive tissue-restricted genes, frequently ectopic expressed in tumors. CTA genes associate with a poor prognosis in some solid tumors, due to their potential roles in the tumorigenesis and progression. However, whether CTAs relate with hepatocellular carcinoma (HCC) remains unclear. In this study, the prognostic signatures based on CTA genes were investigated and validated in three cohorts including Chinese HCC patients with hepatitis B virus infection (CHCC-HBV), International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) cohorts. Univariate, LASSO, and multivariate Cox regression analyses were used to screen prognostic genes and develop the prognostic gene signature. A prognosis model was established with six CTA genes (SSX1, CTCFL, OIP5, CEP55, NOL4, and TPPP2) in CHCC-HBV cohort, and further validated in the ICGC and TCGA cohorts. The CTA signature was an essential prognostic predictor independent of other clinical pathological factors. High-risk group exhibited up-regulated cell cycle-related and tumor-related pathways and more M0 macrophage, activated mast cell, activated memory CD4+ T cell, and memory B cell infiltration. Furthermore, CTA signature correlated with the sensitivity to multiple chemotherapy drugs. Our results highlighted that the CTA gene profiling was a prognostic assessment tool for HCC patients.

Bone metastasis in a novel breast cancer mouse model containing human breast and human bone.

In practice, investigations for bone metastasis of breast cancer rely heavily on models in vivo. Lacking of such ideal model makes it difficult to study the whole process or accurate mechanism of each step of this metastatic disease. Development of xenograft mouse models has made great contributions in this area. Currently, the best animal model of breast cancer metastasizing to bone is NOD/SCID-hu models containing human bone, which makes it possible to let the breast cancer cells and the bone target of osteotropic metastasis be both of human origin. We have developed a novel mouse model containing both human bone and breast, and proved it functional and reliable. In this study, a set of human breast cancer cell line including MDA-MB-231, MDA-MB-231BO, MCF-7, ZR-75-1 and SUM1315 were characterized their osteotropism in this model. A specific cell line SUM1315 made species-specific bone metastasis, certifying the osteotropism-identification utility of the novel mouse model. Furthermore, gene expression and microRNA expression profiling analysis were done to the two SUM1315 derived sub lines isolated and purified from the orthotopic and metastatic xenograft. In addition, to demonstrate the disparity between the "spontaneous" and "forced" bone metastasis in mouse model, MDA-MB-231 cells were inoculated into both the human implants in this model simultaneously, and then primary cultured and profiling analyzed. Supported by overall results of profiling analyses, this study suggested the novel model was a useful tool for understanding, preventing and treating bone metastasis of breast cancer, meanwhile it had provided significant information for further investigations.

Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients.

BACKGROUND: Mounting clinical and experimental data suggest that the migration of tumor cells into lymph nodes is greatly facilitated by lymphangiogenesis. Vascular endothelial growth factor (VEGF)-C and D have been identified as lymphangiogenic growth factors and play an important role in tumor lymphangiogenesis. The purpose of this study was to investigate the location of lymphangiogenesis driven by tumor-derived VEGF-C/D in breast cancer, and to determine the role of intratumoral and peritumoral lymphatic vessel density (LVD) in lymphangiogenesis in breast cancer. METHODS: The expression levels of VEGF-C/D were determined by immunohistochemistry, and intratumoral LVD and peritumoral LVD were assessed using immunohistochemistry and the D2-40 antibody in 73 patients with primary breast cancer. The associations of intratumoral LVD and peritumoral LVD with VEGF-C/D expression, clinicopathological features and prognosis were assessed. RESULTS: VEGF-C and D expression were significantly higher in breast cancer than benign disease (P < 0.01). VEGF-C (P < 0.001) and VEGF-D (P = 0.005) expression were significantly associated with peritumoral LVD, but not intratumoral LVD. Intratumoral LVD was associated with tumor size (P = 0.01). Peritumoral LVD was significantly associated with lymph node metastasis (LNM; P = 0.005), lymphatic vessel invasion (LVI; P = 0.017) and late tumor,node, metastasis (TNM) stage (P = 0.011). Moreover, peritumoral LVD was an independent risk factor for axillary lymph node metastasis, overall survival and disease-free survival in multivariate analysis. CONCLUSIONS: This study suggests that tumor-derived VEGF-C/D induce peritumoral lymphangiogenesis, which may be one mechanism that leads to lymphatic invasion and metastatic spread. Peritumoral LVD has potential as an independent prognostic factor in breast cancer patients.

Biliverdin reductase B impairs cholangiocarcinoma cell motility by inhibiting the Notch/Snail signaling pathway.

Cholangiocarcinoma (CCA) is one of the most lethal types of solid tumors worldwide. Lymph node metastasis is common in the early stage, which is associated with recurrence and reduced survival time after CCA resection. The molecular pathogenesis of CCA is complex and requires extensive investigation. It involves multiple genomic alterations and the dysregulation of signaling pathways. Biliverdin reductase B (BLVRB) is a non-redundant NAD(P)H-dependent biliverdin reductase that regulates cellular redox status by reducing biliverdin to bilirubin. This study aimed at describing the biological functions and molecular mechanisms of BLVRB in human CCA. Prognostic clinical data showed that low expression BLVRB was associated with poor prognosis and lymph node metastasis. BLVRB depletion accelerated epithelial-mesenchymal transition (EMT), cell migration and invasion. In contrast, BLVRB overexpression was associated with reduced EMT and cell migration and invasion in CCA. BLVRB suppression activated Notch signaling, and activated c-Notch enhanced EMT by upregulating Snail expression levels, thereby increasing cell migration and invasion in CCA. Our results identified an unexpected function of BLVRB in CCA migration and invasion through the regulation of Notch/Snail signaling.

ERBB2 S310F mutation independently activates PI3K/AKT and MAPK pathways through homodimers to contribute gallbladder carcinoma growth.

Genomic instability and mutability are a prominent character of tumor. The whole-exosome sequence reveals that ERBB2 mutations are the representative mutations of gallbladder carcinoma, which takes potential targets for gallbladder carcinoma therapy. However, the roles of ERBB2 mutations are unclear in gallbladder carcinoma. We identified S310F mutation is the hottest mutation of ERBB2 mutations from TCGA PanCancer Altas data with 10,967 samples and our previous study with 157 gallbladder carcinoma samples. S310F mutation located in ERBB2 extracellular domain, promoted ERBB2 homodimerization and consequent auto-phosphorylation to activate the downstream PI3K/AKT and MAPK pathways, which was independent on ERBB1, ERBB3, and ERBB4. ERBB2 S310F mutation up-regulated aerobic glycolysis and promoted gallbladder carcinoma growth. Our study reveals the roles of ERBB2 S310F mutation, which is beneficial to ERBB2 S310F mutant gallbladder carcinoma therapy.

Acetylation stabilizes stathmin1 and promotes its activity contributing to gallbladder cancer metastasis.

Gallbladder cancer is the most common biliary tract malignant tumor with highly metastatic characters and poor prognosis. However, the underlying mechanism remains unclear. Stathmin1 is ubiquitous phosphoprotein, regulating microtubule stabilization. We identified the acetylation of stahtmin1 at lysine 9 (K9) in gallbladder cancer. K9 acetylation of stathmin1 was reversely regulated by the acetyltransferase PCAF and the deacetylases sirt2. K9 acetylation of stathmin1 inhibited the combining of stathmin1 to E3 ubiquitin ligase RLIM, thereby inhibiting its ubiquitination degradation. Moreover, K9 acetylation also promoted the activity of stahtmin1 interacting and destabilizing microtubule through the inhibition of stathmin1 phosphorylation. K9 acetylated stathmin1 significantly promoted gallbladder cancer cell migration and invasion viability in vitro and lung metastasis in vivo, and indicated poor prognosis of nude mice. IHC assay suggested the positive correlation of high levels of K9 acetylation and stathmin1 expression in gallbladder cancer. Our study revealed that K9 acetylation up-regulated stathmin1 protein stability and microtubule-destabilizing activity to promoted gallbladder cancer metastasis, which provides a potential target for gallbladder cancer therapy.