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.

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.

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.

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.

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.

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.

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.

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.

Erratum: lncRNA RP11-147L13.8 suppresses metastasis and chemo-resistance by modulating the phosphorylation of c-Jun protein in GBC.

[This corrects the article DOI: 10.1016/j.omto.2021.08.016.].

Samonella typhi infection-related appendicitis: A case report.

BACKGROUND: Acute appendicitis is one of the most common acute abdominal emergencies around the world, which is always associated with infection. Infection with Salmonella typhi, an enteric pathogen, is a rare cause of acute appendicitis. We here report a patient with acute appendicitis associated with Samonella typhi infection, accompanied with spleen and kidney infarction, providing a rare example for a common surgical emergency. CASE SUMMARY: A 25-year-old Pakistani man presented to the hospital with a 3-d history of fevers, vomiting, and abdominal pain. Computed tomography (CT) revealed a thickened intestinal wall of the ileocecal junction with multiple enlarged lymph nodes nearby. He was diagnosed with acute appendicitis and received laparoscopic appendectomy, which showed mild inflammation of the appendix. After the surgery, the patient presented again with a high fever (> 39 °C) and diarrhea. A CT angiography scan indicated spleen and kidney infarction. According to the blood culture, the diagnosis was finally clear to be Samonella typhi infection. The pyrexia and enteric symptoms were relieved after the application of intravenous levofloxacin. CONCLUSION: This case, characterized by the combination of Salmonella typhi infection, acute appendicitis, and renal and splenic infraction, serves as a rare example for a common surgical emergency.

lncRNA RP11-147L13.8 suppresses metastasis and chemo-resistance by modulating the phosphorylation of c-Jun protein in GBC.

Long non-coding RNAs (lncRNAs) have been identified as critical contributors in tumor progression for many types of cancer. However, their functions in gallbladder cancer (GBC) have not been systematically clarified. In this study, the clinical significance, biological function, and underlying mechanism of lncRNA RP11-147L13.8 in GBC were investigated. The quantitative real-time PCR result indicated that lncRNA RP11-147L13.8 was found to be recurrently downregulated in GBC tumor samples. Kaplan-Meier analysis revealed that decreased lncRNA RP11-147L13.8 expression level was associated with poor survival of GBC patients (p = 0.025). Then, both in vitro and in vivo experiments elucidated that the overexpression of lncRNA RP11-147L13.8 suppressed the migration and invasion abilities of GBC cells and promoted the sensitivity to gemcitabine of GBC cells. Furthermore, we found that lncRNA RP11-147L13.8 physically interacted with c-Jun protein and decreased the phosphorylation on serine-73 (c-Jun-Ser73), which might cause the enhancement of the migration, invasion, and sensitivity to gemcitabine of GBC tumor cells. In conclusion, our study identified lncRNA RP11-147L13.8 as a promising prognostic indicator for patients with GBC, providing insights into the molecular pathogenesis of GBC. lncRNA RP11-147L13.8 is a potential therapeutic combination for gemcitabine in GBC treatment.

A Novel Prognostic Biomarker of Luminal Breast Cancer: High CD39 Expression Is Related to Poor Survival.

BACKGROUND: CD39 is one of the functional surface markers for T regulatory cells, the prognostic role and immune-related effects of CD39 in luminal breast cancer (BC) patients has not been evaluated yet. The aim of the current study was to explore the association between CD39 expression and clinic pathological characteristics and the prognosis in luminal BC patients. METHODS: Clinical information and RNA-sequencing (RNA-Seq) expression data were extracted from The Cancer Genome Atlas (TCGA). Patients were divided into a high or low CD39 expression group by the optimal cutoff value (4.18) identified from the receiver operating characteristic curve analysis. The relationships between CD39 expression and clinic pathological features were evaluated by the corresponding statistical tests. Survival analyses were applied to evaluate the overall survival between the high and low CD39 expression groups in luminal BC. Furthermore, Gene Expression Omnibus datasets were used for external data validation. Gene set enrichment analysis (GSEA) was also performed, and CIBERSORT was used to analyze the immune cell populations. RESULTS: Analysis of 439 cases of tumor data showed that CD39 was overexpressed in luminal BC. The multivariable analysis suggested that CD39 expression was an independent prognostic factor for luminal BC patients. GSEA suggested that CD39 might play an important role in luminal BC progression through immune regulation. Analysis of immune cell patterns revealed high CD39 expression correlated to a higher proportion of CD8+ T cells and M2 macrophages. CONCLUSION: This study demonstrates that CD39 expression correlates with the prognosis of luminal BC through TCGA database mining. Further studies are warranted further to elucidate this potential novel therapeutic strategy for BC.

The Biological Function of TUSC7/miR-1224-3p Axis in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancers (TNBC), comprising about 20% of breast cancers, have a poor prognosis. Currently, there is no effective target therapy for TNBC. LncRNA TUSC7 has been identified as a tumor suppressor in osteosarcoma and colorectal cancer. In this study, we investigated the clinical significance and the biological function of TUSC7 in breast cancer. METHODS: We retrospectively evaluated the expression level and clinical significance of TUSC7 in 90 paired breast cancer tissues and normal tissues. The proliferation, migration, and invasion assays were performed to investigate the biological function of TUSC7 in breast cancer. Finally, microarray, a luciferase reporter assay, and quantitative real-time polymerase chain reaction (qPCR) were used to explore the potential underlying mechanism of tumor suppressor role of TUSC7. RESULTS: Low TUSC7 expression was found to be an independent prognostic factor of poor overall survival (OS) in TNBC patients. Ectopic expression of TUSC7 inhibited tumor cell growth both in vitro and in vivo. TUSC7 overexpression significantly promoted the sensitivity of MDA-MB-468 cells to paclitaxel and carboplatin. In terms of the mechanism, TUSC7 might perform its biological function through binding with miR-1224-3P and regulating its expression level. Besides, genes in cell cycle pathways, such as BUB3 (budding uninhibited by benzimidazoles 3) and TGF-ß (targeting transforming growth factor ß) pathways were downregulated, and genes involved in the MAPK (mitogen-activated protein kinase) (TGFBR2, transforming growth factor-beta receptor 2), PI3K-AKT (phosphoinositide 3-kinase- AKT serine/threonine kinase 1) and NF-κB (nuclear factor-kappa B subunit) pathways were upregulated in TUSC7 knockdown MDA-MB-231 cells. CONCLUSION: The low TUSC7 expression is an independent prognostic factor of poor OS of TNBC patients. TUSC7 might inhibit breast cancer cell growth and metastasis both in vitro and vivo through binding with miR-1224-3P and regulating MAPK, PI3K/AKT, and NF-κB signaling pathways.

Adjuvant Therapy in Resected Nonmetastatic Stage II-IV Gallbladder Cancer: A Generalized Propensity Score Analysis.

BACKGROUND: The clinical benefits and efficacies of adjuvant therapies for gallbladder cancer (GBC) have not been verified due to insufficient clinical evidence. METHODS: Patients with resected nonmetastatic stage II-IV GBC were selected from the Surveillance, Epidemiology, and End Results database and distributed into nonchemotherapy and chemoradiotherapy (NCRT), chemotherapy (CT), and chemoradiotherapy (CRT) groups. Generalized propensity score and inverse probability of treatment weighting (IPTW) were used to reduce the imbalances between groups. RESULTS: A total of 2,689 patients were enrolled, among whom 1,193 (44.4%) were classified as stage II, 1,371 (51.0%) as stage III, and 125 (4.6%) as stage IV GBC. A total of 1,703, 444, and 542 patients were placed in the NCRT, CT, and CRT groups, respectively. After the IPTW, there were no significant differences in overall survival (OS) between the 3 treatment groups (p > 0.05) in stage II GBC patients. In patients with stage III-IV GBC, the CT group exhibited a superior OS compared to the NCRT group (p < 0.001). In addition, the CRT group exhibited a superior OS compared to the CT (p < 0.001) and NCRT (p < 0.001) groups. For patients with stage III-IV tumors, a nomogram was constructed to predict the survival benefits of adjuvant therapies. CONCLUSION: Patients with stage II GBC may not benefit from adjuvant therapy, while patients with stage III-IV GBC were shown to benefit from chemotherapy and chemoradiotherapy. Furthermore, chemoradiotherapy exhibited a superior OS. Nevertheless, the results need to be explained in the context of retrospective studies.

Long noncoding RNA ENST00000508435 promotes migration of breast cancer via FXR 1.

LncRNA plays a critical role in tumor progression. However, the role it executes in breast cancer is still unclear. Here, we report a newly discovered lncRNA, ENST00000508435, which could be remarkably up-regulated in breast cancer cells and tissues. We found that the expression of ENST00000508435 was positively correlated with tumor size, lymph node metastasis and HER2. More interesting, overexpression of ENST00000508435 significantly increased cell migration, while specific knockdown led to the opposite. RNA pull-down and RNA immunoprecipitation assays demonstrated that ENST00000508435 could directly bind to FXR1 to promote tumor metastasis. ENST00000508435 and FXR1 were positively correlated. FXR1 was also significantly up-regulated in breast tumors. Taken together, we propose that ENST00000508435 regulates FXR1 to promote breast cancer metastasis.

SEC61G promotes breast cancer development and metastasis via modulating glycolysis and is transcriptionally regulated by E2F1.

Breast cancer is the most common cancer in women and its incidence rates are rapidly increasing in China. Understanding the molecular mechanisms of breast cancer tumorigenesis enables the development of novel therapeutic strategies. SEC61G is a subunit of the endoplasmic reticulum translocon that plays critical roles in various tumors. We aimed to investigate the expression and function of SEC61G in breast cancer. By analyzing The Cancer Genome Atlas breast cancer cohort, we found that SEC61G was highly expressed in breast cancer and predicted poor prognosis of breast cancer patients. Overexpression of SEC61G and its prognostic role was also confirmed in the Nanjing Medical University (NMU) breast cancer cohort. Functionally, we demonstrated that knockdown of SEC61G suppressed breast cancer cell proliferation, migration, invasion, and promoted breast cancer cell apoptosis in vitro. Xenograft breast tumor model revealed that knockdown of SEC61G inhibited breast tumor development in vivo. Furthermore, we demonstrated that SEC61G positively regulated glycolysis in breast cancer cells. Mechanistically, we showed that transcription factor E2F1 directly bound to the promoter of SEC61G and regulated its expression in breast cancer cells. SEC61G overexpression antagonized the effect of E2F1 knockdown in regulating breast cancer cell proliferation, invasion, and apoptosis. Finally, we demonstrated that the E2F1/SEC61G axis regulated glycolysis and chemo-sensitivity of Herceptin in breast cancer cells. Taken together, these results of in vitro and in vivo studies demonstrate that SEC61G promotes breast cancer development and metastasis via modulating glycolysis and is transcriptionally regulated by E2F1, which might be utilized as a promising therapeutic target of breast cancer treatment.

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.

Phosphorylation at Ser10 triggered p27 degradation and promoted gallbladder carcinoma cell migration and invasion by regulating stathmin1 under glucose deficiency.

Gallbladder carcinoma (GBC) is a considerable challenge because of its high metastatic potential. The tumor microenvironment is characterized by nutrient starvation, which promotes tumor metastasis. Stathmin1, an important microtubuleregulating protein, is overexpressed and promotes metastasis in GBC. It remains unclear how the harsh tumor microenvironment regulates stathmin1 expression to affect GBC metastasis. We employed glucose deficiency to mimic nutrient starvation and found that glucose deficiency upregulated stathmin1 transcription. However, glucose deficiency also promoted p27 degradation. There was a significant negative correlation between stathmin1 and p27 protein levels under glucose deficiency. Further study revealed that, under glucose deficiency, human kinase interacting with stathmin (hKIS) induced phosphorylation at Ser10 of p27 and its translocation to the cytoplasm for degradation, which upregulated the transcription factor E2F1 to promote stathmin1 transcription. hKIS knockdown significantly inhibited p27 cytoplasmic translocation and its consequent degradation. Stathmin1 knockdown significantly inhibited GBC cell migration and invasion in vitro. Our study revealed the role of the hKIS/p27/E2F1 axis in upregulating stathmin1 transcription to promote GBC cell migration and invasion under glucose deficiency conditions.