Serine/threonine-protein kinase D2-mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression.

Desmoglein-2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell-cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine-protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2-T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2-mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

Secreted proteins encoded by super enhancer-driven genes could be promising biomarkers for early detection of esophageal squamous cell carcinoma.

BACKGROUND: Early detection of cancer remains an unmet need in clinical practice, and high diagnostic sensitivity and specificity biomarkers are urgently required. Here, we attempted to identify secreted proteins encoded by super-enhancer (SE)-driven genes as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC). METHODS: We conducted an integrative analysis of multiple data sets including ChIP-seq data, secretome data, CCLE data and GEO data to screen secreted proteins encoded by SE-driven genes. Using ELISA, we further identified up-regulated secreted proteins through a small size of clinical samples and verified in a multi-centre validation stage (345 in test cohort and 231 in validation cohort). Receiver operating characteristic curves were used to calculate diagnostic accuracy. Artificial intelligence (AI) method named gradient boosting machine (GBM) were applied for model construction to enhance diagnostic accuracy. RESULTS: Serum EFNA1 and MMP13 were identified, and showed significantly higher levels in ESCC patients compared to normal controls. An integrated Five-Biomarker Panel (iFBPanel) established by combining EFNA1, MMP13, carcino-embryonic antigen, Cyfra21-1 and squmaous cell carcinoma antigen had AUCs of 0.881 and 0.880 for ESCC in test and validation cohorts, respectively. Importantly, the iFBPanel also exhibited good performance in detecting early-stage ESCC patients (0.872 and 0.864). Furthermore, the iFBPanel was further empowered by AI technology which showed excellent diagnostic performance in early-stage ESCC (0.927 and 0.907). CONCLUSIONS: Our study suggested that serum EFNA1 and MMP13 could potentially assist ESCC detection, and provided an easy-to-use detection model that might help the diagnosis of early-stage ESCC.

EFNA1 in gastrointestinal cancer: Expression, regulation and clinical significance.

Ephrin-A1 is a protein that in humans is encoded by the EFNA1 gene. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases which play an indispensable role in normal growth and development or in the pathophysiology of various tumors. The role of EFNA1 in tumorigenesis and development is complex and depends on the cell type and microenvironment which in turn affect the expression of EFNA1. This article reviews the expression, prognostic value, regulation and clinical significance of EFNA1 in gastrointestinal tumors.

Serum DSG2 as a potential biomarker for diagnosis of esophageal squamous cell carcinoma and esophagogastric junction adenocarcinoma.

BACKGROUND: Exploration of serum biomarkers for early detection of upper gastrointestinal cancer is required. Here, we aimed to evaluate the diagnostic potential of serum desmoglein-2 (DSG2) in patients with esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EJA). METHODS: Serum DSG2 levels were measured by enzyme-linked immunosorbent assay (ELISA) in 459 participants including 151 patients with ESCC, 96 with EJA, and 212 healthy controls. Receiver operating characteristic (ROC) curves were used to evaluate diagnostic accuracy. RESULTS: Levels of serum DSG2 were significantly higher in patients with ESCC and EJA than those in healthy controls (P<0.001). Detection of serum DSG2 demonstrated an area under the ROC curve (AUC) value of 0.724, sensitivity of 38.1%, and specificity of 84.8% for the diagnosis of ESCC in the training cohort, and AUC 0.736, sensitivity 58.2%, and specificity 84.7% in the validation cohort. For diagnosis of EJA, measurement of DSG2 provided a sensitivity of 29.2%, a specificity of 90.2%, and AUC of 0.698. Similar results were observed for the diagnosis of early-stage ESCC (AUC 0.715 and 0.722, sensitivity 36.3 and 50%, and specificity 84.8 and 84.7%, for training and validation cohorts, respectively) and early-stage EJA (AUC 0.704, sensitivity 44.4%, and specificity 86.9%). Analysis of clinical data indicated that DSG2 levels were significantly associated with patient age and histological grade in ESCC (P<0.05). CONCLUSION: Serum DSG2 may be a diagnostic biomarker for ESCC and EJA.

Role of Integrin ß1 in the progression and chemo-resistance of esophageal squamous cell carcinoma.

Objective: Integrins have been shown to play an important role in the tumorigenesis of many cancers. In this work, we aimed to explore the expression and clinical value of Integrin α5ß1 in esophageal squamous cell carcinoma (ESCC), and the effect of integrin ß1 on the development and chemo-resistance of ESCC cells. Methods: The expression profiling of integrins was analyzed in the mRNA expression dataset of ESCC. The expression of Integrin α5ß1 in 278 cases of ESCC tissues and 62 cases of paracancerous tissues was detected by immunohistochemistry (IHC). The association between the expression of Integrin α5ß1 and the survival of ESCC patients was analyzed by Kaplan-Meier analysis. The effect of Integrin ß1 on the proliferation, migration, and invasion of ESCC cells was examined by MTS, Transwell migration, and Transwell invasion assay. The effect of Integrin ß1 and L1 cell adhesion molecule (L1CAM) on cisplatin resistance was detected by MTS and the signal pathways involved were analyzed by Western blotting. Results: Integrin ß1 and Integrin α5 were significantly up-regulated in ESCC. High expression of Integrin ß1 was also related to worse overall survival of ESCC patients and patients with low levels of both Integrin ß1 and Integrin α5 showed the shortest survival. Results of IHC revealed that Integrin α5ß1 was up-regulated in ESCC and its high expression was associated with poor prognosis and could serve as an independent prognostic factor. siRNA-mediated Integrin ß1 silencing or antibody blocking restrained the proliferation, migration, and invasion of ESCC cells. Simultaneous knockdown of Integrin ß1 and L1CAM reduced the cisplatin resistance of ESCC cells. Further studies showed that knockdown of Integrin ß1 and L1CAM suppressed the activity of Akt signaling with or without cisplatin treatment. Moreover, dual high expression of Integrin ß1 and L1CAM was related to worse overall survival of ESCC patients treated with preoperative chemotherapy. Conclusion: Integrin α5ß1 was up-regulated in ESCC and could be used as a new prognostic indicator for ESCC patients. In addition, Integrin ß1 was involved in the proliferation, invasion, and chemo-resistance of ESCC cells.

Construction of the Six-lncRNA Prognosis Signature as a Novel Biomarker in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common malignant gastrointestinal tumor threatening global human health. For patients diagnosed with ESCC, determining the prognosis is a huge challenge. Due to their important role in tumor progression, long non-coding RNAs (lncRNAs) may be putative molecular candidates in the survival prediction of ESCC patients. Here, we obtained three datasets of ESCC lncRNA expression profiles (GSE53624, GSE53622, and GSE53625) from the Gene Expression Omnibus (GEO) database. The method of statistics and machine learning including survival analysis and LASSO regression analysis were applied. We identified a six-lncRNA signature composed of AL445524.1, AC109439.2, LINC01273, AC015922.3, LINC00547, and PSPC1-AS2. Kaplan-Meier and Cox analyses were conducted, and the prognostic ability and predictive independence of the lncRNA signature were found in three ESCC datasets. In the entire set, time-dependent ROC curve analysis showed that the prediction accuracy of the lncRNA signature was remarkably greater than that of TNM stage. ROC and stratified analysis indicated that the combination of six-lncRNA signature with the TNM stage has the highest accuracy in subgrouping ESCC patients. Furthermore, experiments subsequently confirmed that one of the lncRNAs LINC01273 may play an oncogenic role in ESCC. This study suggested the six-lncRNA signature could be a valuable survival predictor for patients with ESCC and have potential to be an auxiliary biomarker of TNM stage to subdivide ESCC patients more accurately, which has important clinical significance.

Paradoxical Roles of Desmosomal Components in Head and Neck Cancer.

Desmosomes are intercellular adhesion complexes involved in various aspects of epithelial pathophysiology, including tissue homeostasis, morphogenesis, and disease development. Recent studies have reported that the abnormal expression of various desmosomal components correlates with tumor progression and poor survival. In addition, desmosomes have been shown to act as a signaling platform to regulate the proliferation, invasion, migration, morphogenesis, and apoptosis of cancer cells. The occurrence and progression of head and neck cancer (HNC) is accompanied by abnormal expression of desmosomal components and loss of desmosome structure. However, the role of desmosomal components in the progression of HNC remains controversial. This review aims to provide an overview of recent developments showing the paradoxical roles of desmosomal components in tumor suppression and promotion. It offers valuable insights for HNC diagnosis and therapeutics development.

Serum CYR61 as a potential biomarker for the diagnosis of esophagogastric junction tumor.

BACKGROUND: Esophagogastric junction tumor (EGJ) is a rare but fatal disease with a rapid rising incidence worldwide in the late 20 years, and it lacks a convenient and safe method for diagnosis. The present study aimed to evaluate the potential of serum CYR61 as a biomarker for the diagnosis of EGJ tumor. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to estimate CYR61 levels in sera of 152 EGJ tumor patients and 137 normal controls. Receiver operating characteristics (ROC) was carried out to evaluate the diagnostic accuracy. The Mann-Whitney's U test was used to compare the difference of serum levels of CYR61 between groups. And chi-square tests were employed to estimate the correlation of the positive rate of serum CYR61 between/among subgroups. RESULTS: Serum CYR61 levels were statistically lower in EGJ tumor and early-stage EGJ tumor patients than those in normal controls (P<0.0001). The sensitivity, specificity and the area under the curve (AUC) of this biomarker in EGJ tumor were 88.2%, 43.8% and 0.691, respectively, and those for early stage of EGJ tumor were 80.0%, 66.4% and 0.722, respectively. Analyses showed that there was no correlation between the clinical data and the levels of CYR61 (P>0.05). CONCLUSION: The present study showed that CYR61 might be a potential biomarker to assist the diagnosis of EGJ tumor.

Diagnostic Value of Serum Insulin-Like Growth Factor Binding Protein 7 (IGFBP7) in Colorectal Cancer.

PURPOSE: High serum insulin-like growth factor binding protein-7 (IGFBP-7) has been found in several malignant tumors. Here, we aimed to assess the diagnostic potential of serum IGFBP7 in patients with colorectal cancer (CRC). PATIENTS AND METHODS: An enzyme-linked immunosorbent assay (ELISA) was performed to detect IGFBP7 level in the serum of 115 CRC patients and 107 healthy controls, and receiver operating characteristics (ROC) was used to evaluate the accuracy of diagnosis. RESULTS: The levels of serum IGFBP7 were significantly higher in CRC than those in normal controls (P < 0.001). With optimized cutoff of 2.050 ng/mL, IGFBP7 showed certain diagnostic value with specificity of 93.9%, sensitivity of 64.5% and an area under the curve (AUC) of 0.815 (95% CI: 0.754-0.877) in CRC. In early-stage CRC, IGFBP7 provided an AUC of 0.826 (95% CI: 0.757-0.896), a sensitivity of 64.5%, and a specificity of 95.8%. Furthermore, when compared with carcinoembryonic antigen (CEA), the accuracy of serum IGFBP7 in the diagnosis of CRC and early-stage CRC were significantly improved. Analysis of clinical data shows that there are no significant differences between IGFBP7 and clinical factors. CONCLUSION: Our study suggested that serum IGFBP7 might serve as a potential biomarker for early-stage CRC diagnosis.

Circulating Levels of L1-cell Adhesion Molecule as a Serum Biomarker for Early Detection of Gastric Cancer and Esophagogastric Junction Adenocarcinoma.

Background: Low serum L1 cell adhesion molecule (L1CAM) has been found in several malignant tumors. Here, we aimed to evaluate the diagnostic potential for serum L1CAM in patients with gastric cancers (GC) and esophagogastric junction adenocarcinoma (EJA). Methods: Enzyme-linked immunosorbent assay (ELISA) was carried out to detect L1CAM level in sera of 148 GC patients, 59 EJA patients and 148 healthy controls. Receiver operating characteristics (ROC) was employed to evaluate diagnostic accuracy. Results: The concentrations of serum L1CAM were significantly lower in GC and EJA than those in healthy controls (P<0.001). Detection of L1CAM provided a sensitivity of 83.1%, a specificity of 62.2%, and an area under the curve (AUC) of 0.769 (95% CI: 0.715-0.823) in diagnosing GC, and a sensitivity of 66.1%, a specificity of 62.2%, and an AUC of 0.672 (95% CI: 0.590-0.755) in diagnosing EJA. Similar results were observed in the diagnosis of early-stage GC (0.681 (95%CI: 0.596-0.766)) and early-stage EJA (0.674 (95%CI: 0.528-0.820)). Analysis of clinical data showed that the levels of L1CAM were significantly associated with lymph node metastasis in GC (P<0.05). Conclusions: Our study showed that serum L1CAM might be a diagnostic biomarker for GC and EJA.

TP63, SOX2, and KLF5 Establish a Core Regulatory Circuitry That Controls Epigenetic and Transcription Patterns in Esophageal Squamous Cell Carcinoma Cell Lines.

BACKGROUND & AIMS: We investigated the transcriptome of esophageal squamous cell carcinoma (ESCC) cells, activity of gene regulatory (enhancer and promoter regions), and the effects of blocking epigenetic regulatory proteins. METHODS: We performed chromatin immunoprecipitation sequencing with antibodies against H3K4me1, H3K4me3, and H3K27ac and an assay for transposase-accessible chromatin to map the enhancer regions and accessible chromatin in 8 ESCC cell lines. We used the CRC_Mapper algorithm to identify core regulatory circuitry transcription factors in ESCC cell lines, and determined genome occupancy profiles for 3 of these factors. In ESCC cell lines, expression of transcription factors was knocked down with small hairpin RNAs, promoter and enhancer regions were disrupted by CRISPR/Cas9 genome editing, or bromodomains and extraterminal (BET) family proteins and histone deacetylases (HDACs) were inhibited with ARV-771 and romidepsin, respectively. ESCC cell lines were then analyzed by whole-transcriptome sequencing, immunoprecipitation, immunoblots, immunohistochemistry, and viability assays. Interactions between distal enhancers and promoters were identified and verified with circular chromosome conformation capture sequencing. NOD-SCID mice were given injections of modified ESCC cells, some mice where given injections of HDAC or BET inhibitors, and growth of xenograft tumors was measured. RESULTS: We identified super-enhancer-regulated circuits and transcription factors TP63, SOX2, and KLF5 as core regulatory factors in ESCC cells. Super-enhancer regulation of ALDH3A1 mediated by core regulatory factors was required for ESCC viability. We observed direct interactions between the promoter region of TP63 and functional enhancers, mediated by the core regulatory circuitry transcription factors. Deletion of enhancer regions from ESCC cells decreased expression of the core regulatory circuitry transcription factors and reduced cell viability; these same results were observed with knockdown of each core regulatory circuitry transcription factor. Incubation of ESCC cells with BET and HDAC disrupted the core regulatory circuitry program and the epigenetic modifications observed in these cells; mice given injections of HDAC or BET inhibitors developed smaller xenograft tumors from the ESCC cell lines. Xenograft tumors grew more slowly in mice given the combination of ARV-771 and romidepsin than mice given either agent alone. CONCLUSIONS: In epigenetic and transcriptional analyses of ESCC cell lines, we found the transcription factors TP63, SOX2, and KLF5 to be part of a core regulatory network that determines chromatin accessibility, epigenetic modifications, and gene expression patterns in these cells. A combination of epigenetic inhibitors slowed growth of xenograft tumors derived from ESCC cells in mice.

ApoB/ApoA-1 Ratio as a Novel Prognostic Predictor in Patients With Primary Small Cell Carcinoma of the Esophagus.

Background and Aim: Primary small cell carcinoma of the esophagus (SCCE) is a rarely aggressive disease characterized by rapid progression, widespread metastasis, and poor prognosis. This study was aimed to evaluate the prognostic significance of serum lipids for overall survival (OS) in SCCE patients. Methods: We retrospectively analyzed SCCE patients in a training cohort (61 patients) and validated them in a validation cohort (27 patients). These cases were collected from Sun Yat-sen University Cancer Center from 2006 to 2017. Univariate and multivariate Cox survival analyses were performed to determine serum lipids as prognostic factors associated with the patient's OS. Time-dependent receiver operating characteristics (ROC) were used to compare predictive power of independent prognostic factors. The predictive accuracy and discriminative ability of the prognostic factors were measured by the concordance index (C-index) and decision curve, and were compared with the TNM stage system. Results: On multivariate analysis of the training cohort, independent factors for survival were gender, BAR (ApoB/ApoA-1) and TNM stage. The area under the curve (AUC) of BAR+TNM stage in the training cohort was higher than that of TNM stage for OS, and similar result was observed in the validation cohort. The c-index of BAR+TNM stage for predicting the OS was 0.655 (95% CI = 0.571-0.740), which was higher than that of TNM stage [0.614 (95% CI = 0.530-0.698)] in the training cohort. In the validation cohort, the C-index of the BAR+TNM stage for predicting OS was also higher than that of the TNM stage [0.688 (95% CI: 0.570~0.806) vs. (0.512; 95% CI: 0.392~0.632)]. In addition, decision curve analysis also showed that the predictive accuracy of BAR+TNM stage for OS was higher than TNM stage both in the training and the validation cohorts. Conclusions: BAR represents a promising prognostic indicator that might complement TNM stage in the prognosis of SCCE, and that warrant further assessment in large SCCE patient cohort.

Blood-based biomarkers for early detection of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive system worldwide, especially in China. Due to the lack of effective early detection methods, ESCC patients often present at an advanced stage at the time of diagnosis, which seriously affects the prognosis of patients. At present, early detection of ESCC mainly depends on invasive and expensive endoscopy and histopathological biopsy. Therefore, there is an unmet need for a non-invasive method to detect ESCC in the early stages. With the emergence of a large class of non-invasive diagnostic tools, serum tumor markers have attracted much attention because of their potential for detection of early tumors. Therefore, the identification of serum tumor markers for early detection of ESCC is undoubtedly one of the most effective ways to achieve early diagnosis and treatment of ESCC. This article reviews the recent advances in the discovery of blood-based ESCC biomarkers, and discusses the origins, clinical applications, and technical challenges of clinical validation of various types of biomarkers.

The Diagnostic Value of Serum L1CAM in Patients With Colorectal Cancer.

OBJECTIVE: Colorectal cancer is one of the most important malignant cancer in the world with high incidence and mortality. Some studies have found that the expression of low serum L1 cell adhesion molecule is associated with poor prognosis in some malignancies. It is suggested that L1 cell adhesion molecule is a candidate serum marker for certain tumors. However, the relationship between serum L1 cell adhesion molecule and colorectal cancer, especially about the diagnostic value, is rarely reported. Therefore, this study aimed to evaluate the diagnostic potential of serum L1 cell adhesion molecule in patients with colorectal cancer. METHODS: Enzyme-linked immunosorbent assay was carried out to detect L1 cell adhesion molecule level in sera of 229 patients with colorectal cancer and 145 normal controls. Receiver operating characteristic curves were employed to calculate the accuracy of diagnosis. RESULTS: The levels of serum L1 cell adhesion molecule in the colorectal cancer group were significantly lower than that in normal controls (P < .05). In the normal group, the area under the receiver operating characteristic curve (area under the curve) of all colorectal cancer was 0.781 (95% confidence interval: 0.734-0.828) and early-stage colorectal cancer was 0.764 (95% confidence interval: 0.705-0.823). With optimized cutoff of 17.760 ng/mL, L1 cell adhesion molecule showed certain diagnostic value with specificity of 90.3% and sensitivities of 43.2% and 36.2% in colorectal cancer and early-stage colorectal cancer, respectively. Clinical data analysis showed that the levels of L1 cell adhesion molecule were significantly correlated with gender (P < .05) and early and late stages (P < .05). Furthermore, when compared with carcinoembryonic antigen, serum L1 cell adhesion molecule had significantly improved diagnostic accuracy for both colorectal cancer and early-stage colorectal cancer. CONCLUSIONS: Our study demonstrated that serum L1 cell adhesion molecule might be served as a potential biomarker for the diagnosis of colorectal cancer.

Autoantibodies: Potential clinical applications in early detection of esophageal squamous cell carcinoma and esophagogastric junction adenocarcinoma.

Esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EGJA) are the two main types of gastrointestinal cancers that pose a huge threat to human health. ESCC remains one of the most common malignant diseases around the world. In contrast to the decreasing prevalence of ESCC, the incidence of EGJA is rising rapidly. Early detection represents one of the most promising ways to improve the prognosis and reduce the mortality of these cancers. Current approaches for early diagnosis mainly depend on invasive and costly endoscopy. Non-invasive biomarkers are in great need to facilitate earlier detection for better clinical management of patients. Tumor-associated autoantibodies can be detected at an early stage before manifestations of clinical signs of tumorigenesis, making them promising biomarkers for early detection and monitoring of ESCC and EGJA. In this review, we summarize recent insights into the iden-tification and validation of tumor-associated autoantibodies for the early detection of ESCC and EGJA and discuss the challenges remaining for clinical validation.

Diosgenin inhibits the expression of NEDD4 in prostate cancer cells.

Prostate cancer is the second most common malignancy among men and causes a myriad of health problem for males that are diagnosed with the cancer. Although the 5-year relative survival rate of prostate cancer patients has been significantly increased due to prostate-specific antigen testing and treatment advances, patients that develop metastatic castrate-resistant prostate cancer continue to have poor survival rates. Thus, it is critical to discover new therapeutics to treat prostate cancer. Diosgenin is a steroidal saponin from Trigonella foenum graecum, which has been previously identified to exert anti-tumor properties. Neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) is an E3 ligase that degrades multiple different proteins, and plays an oncogenic role in human cancer. In this study, we explore the molecular mechanism by which diosgenin mediates anti-tumor effects in prostate cancer cells. We found that diosgenin treatment led to cell growth inhibition, apoptosis and cell cycle arrest. Notably, we found that diosgenin inhibited the expression of NEDD4 in prostate cancer cells. Furthermore, overexpression of NEDD4 overcame the diosgenin-mediated anti-tumor activity, while downregulation of NEDD4 promoted the diosgenin-induced anti-cancer function in prostate cancer cells. Our findings indicate that diosgenin is a potential new inhibitor of NEDD4 in prostate cancer cells.

Heat shock protein family B member 1 facilitates ezrin activation to control cell migration in esophageal squamous cell carcinoma.

Ezrin plays an important role in the development and progression of human esophageal squamous cell carcinoma (ESCC), providing a link between the cortical actin cytoskeleton and the plasma membrane to govern membrane structure and protrusions. However, the mechanism by which ezrin is activated still remains unknown in ESCC. Here, we identify a novel interaction between ezrin and heat shock protein family B (small) member 1 (HSPB1) in ESCC cells by mass spectroscopy and co-immunoprecipitation. HSPB1 only interacts with inactive ezrin and binds to the α-helical coiled coil region of ezrin. Knockdown of HSPB1 resulted to the decline of phosphorylation at ezrin Thr567, markedly suppressing the ability of ezrin to bind to the actin cytoskeleton and migration of ESCC cells. Furthermore, neither the constitutively active phosphomimetic ezrin T567D, nor inactivated ezrin T567A could restore cell migration following HSPB1 knockdown. Low HSPB1 expression was associated with favorable overall survival of ESCC patients. Taken together, HSPB1, as an important partner, participates in the activation of ezrin and merits further evaluation as a novel therapeutic target against human ESCC.

[Pelvic MRI combined with TRUS-guided transperineal template mapping biopsy for the diagnosis of prostate cancer].

OBJECTIVE: To assess the clinical value and safety of pelvic MRI combined with transurethral ultrasound (TRUS)-guided transperineal template mapping biopsy (TTMB) in the diagnosis of prostate cancer. METHODS: A total of 164 men underwent MRI plus TRUS-guided TTMB for the diagnosis of prostate cancer from December 2015 to May 2018. The patients averaged 71.2 years of age and, based on the PSA level, were divided into four groups: PSA <10 µg/L (n = 28), PSA 10－20 µg/L (n = 56), PSA 20.01－100 µg/L (n = 53) and PSA >100 µg/L (n = 27). All the patients received digital rectal examination, pelvic MRI and TRUS-guided X+12-core TTMB. RESULTS: The procedures of TRUS-guided TTMB were successfully completed in all the patients, with an average number of 14.2 (14－16) cores and mean operation time of 18 (15－28) minutes. Post-biopsy complications included transient hematuria in 4 cases, perineal hematoma in 12 and fever in 1, but no acute urinary retention. Pathological results revealed 95 cases of prostate cancer, 2 cases of ductal epithelial carcinoma, 63 cases of prostatic hyperplasia with benign interstitial inflammation, and 4 cases of atypical prostatic hyperplasia. The positive biopsy rates in the PSA <10 µg/L, 10－20 µg/L, 20.01－100 µg/L and >100 µg/L groups were 25.00%, 42.86%, 73.58% and 100.00% respectively, with statistically significant difference between the PSA <10 µg/L group and the PSA 20.01－100 µg/L and >100 µg/L groups (P < 0.01), but not between the PSA <10 µg/L and PSA 10－20 µg/L groups (P = 0.086). CONCLUSIONS: Pelvic MRI combined with TRUS-guided X+12-core TTMB, with the advantages of high accuracy and low rate of complications, is an ideal approach to the diagnosis of prostate cancer.

The histone deacetylase inhibitor panobinostat exerts anticancer effects on esophageal squamous cell carcinoma cells by inducing cell cycle arrest.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Histone deacetylase inhibitors (HDACIs) have been demonstrated as an emerging class of anticancer drugs for a range of haematological and solid tumours. However, the effect of HDACIs has not yet been investigated on ESCC cells. In this study, HDACIs were initially considered to have anticancer activity for ESCC, due to the high expression of HDAC genes in ESCC cell lines by analysing expression data of 27 ESCC cell lines from the Broad-Novartis Cancer Cell Line Encyclopedia. Next, we used five ESCC cell lines and one normal immortalized esophageal epithelial cell line to screen three HDACIs, panobinostat (LBH589), vorinostat (SAHA), and trichostatin A (TSA), for the ability to inhibit growth. Here, we report that LBH589 more effectively suppressed cell proliferation of ESCC cell lines, in a dose-dependent manner, than TSA and SAHA, as well as had lower toxicity against the SHEE normal immortalized esophageal epithelial cell line. Further experiments indicated that LBH589 treatment significantly inhibited TP53 (mutated TP53) expression, both at the mRNA and protein level, and simultaneously increased p21 and decreased cyclin D1 expression. Taken together, we propose that LBH589 inhibits ESCC cell proliferation mainly through inducing cell cycle arrest by increasing p21 and decreasing cyclin D1 in a p53-independent manner. SIGNIFICANCE OF THE STUDY: In this study, the antitumor activity of HDACIs LBH589, SAHA, and TSA on ESCC was characterized, with LBH589 displaying the most potent anti-proliferative activity while not harming normal immortalized esophageal epithelial cells. Furthermore, we propose that LBH589 exerts its anti-proliferative effect by inducing cell cycle arrest. The ability to specifically target cancer cells indicates therapeutic potential for use of LBH589 in the treatment of ESCC.

Diagnostic and prognostic value of serum L1-cell adhesion molecule in esophageal squamous cell carcinoma.

OBJECTIVE: L1 cell adhesion molecule (L1CAM) has been found to be dysregulated in several types of human cancers. Here, we aimed to determine the level of soluble L1CAM in serum of patients with esophageal squamous cell carcinoma (ESCC). METHODS: Serum levels of L1CAM were determined by an enzyme-linked immunosorbent assay (ELISA) in 191 patients with ESCC and 94 normal controls. Receiver operating characteristics (ROC) was employed to calculate diagnostic accuracy. Cumulative survival time was calculated by the Kaplan-Meier method and analyzed by the logrank test. RESULTS: Levels of L1CAM were significantly lower in all ESCC patients than in normal controls (P < 0.001). Detection of serum L1CAM provided a sensitivity of 28.3%, a specificity of 90.4% and an area under the curve (AUC) of 0.644 (95% CI: 0.579-0.710) in diagnosing ESCC. Similar results were observed in the diagnosis of early-stage ESCC (26.2% sensitivity, 90.4% specificity, and an AUC of 0.629). Moreover, decreased level of L1CAM was correlated with depth of tumor invasion (P < 0.05). Kaplan-Meier analysis showed that lower serum L1CAM level was significantly related to shorter overall survival time (P = 0.036) and disease-free survival time (P = 0.021) of ESCC patients. CONCLUSIONS: Our study demonstrated that serum L1CAM might serve as a potential biomarker for the diagnosis and prognosis of ESCC.