hes1-protein--human and Esophageal-Squamous-Cell-Carcinoma

As one of the most prevalent and deadly cancers worldwide, esophageal squamous cell carcinoma (ESCC) can be directly exposed to endocrine-disrupting chemical (EDC). As a potential EDC, diethylhexyl phthalate (DEHP) can trigger the development of various cancers, while the potential effect of DEHP on the ESCC progression was not clear. Our present study revealed that DEHP can trigger the proliferation of ESCC cells and decrease the cisplatin (CDDP) and fluorouracil (5-FU) sensitivity. Mechanistical studies indicated that DEHP can decrease the transcription of PTEN, a well-characterized tumor suppressor, in ESCC cells. Over expression of PTEN can reverse DEHP-regulated ESCC cell proliferation and chemosensitivity. Further, DEHP can increase the expression of HES-1, which can bind with the promoter of PTEN to inhibit its transcription. Collectively, DEHP can increase proliferation while decrease chemosensitivity of ESCC cells via regulation of HES-1/PTEN axis. Further, daily expression of DEHP may be a potent risk factor for ESCC development.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cisplatin; Diethylhexyl Phthalate; Disease Progression; Drug Resistance, Neoplasm; Endocrine Disruptors; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Fluorouracil; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Protein Binding; PTEN Phosphohydrolase; Transcription Factor HES-1; Transcription, Genetic

Substance P (SP) plays an important role in several types of cancer promotion and progression by binding to its preferential neurokinin 1 receptor (NK1R). However, the clinical significance and downstream mechanism of NK1R in esophageal squamous cell carcinoma (ESCC) have not been elucidated. The aim of this study was to investigate the role of SP/NK1R in the proliferation of ESCC and to screen related downstream molecules.. In the current investigation, the expression of NK1R was detected via immunohistochemistry (IHC), western blot (WB) analysis and real-time reverse transcription-polymerase chain reaction (RT-qPCR) in ESCC tissues and cell lines. Thereafter, the optimal concentration of SP was determined in vitro. The proliferation ability of SP/NK1R was assessed by cell counting kit-8 (CCK-8) and colony formation assays and subcutaneous tumour formation in nude mice with EC109 cells. Moreover, the related downstream molecules were screened by performing isobaric tags for relative and absolute quantitation (iTRAQ) protein spectrum analysis.. NK1R was upregulated in ESCC, and its overexpression correlated with larger tumour size, deeper tumour invasion, more perineural invasion and eventually caused poorer overall survival (OS). Both intrinsic and SP-activated NK1R upregulation could promote the proliferation and clonogenic capacity of ESCC cells. In nude mice, tumour growth was suppressed by EC109 cells of NK1R downregulation. Further experiments demonstrated that Hairy and Enhancer of Split 1 (Hes1) was markedly reduced upon NK1R downregulation in EC109 cell lines and could regulate cell proliferation in the downstream of SP/NK1R.. The significant role of NK1R in mediating ESCC cell proliferation depended on the activation of SP and might be related to the downstream regulation of Hes1.

Topics: Animals; Cell Proliferation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; Mice; Receptors, Neurokinin-1; Substance P; Transcription Factor HES-1; Tumor Cells, Cultured

Notch signaling is one of the main involved pathways in cell differentiation and organogenesis, and its deregulation may lead to tumorigenesis. In this pathway, targeted to the CSL (CBF1, Suppressor of Hairless or Lag-1) complex, notch intracellular domain (NICD) releases corepressors and recruits MAML1 as coactivator triggering the activation of notch signaling transcription complex. Hairy enhance of split-1 (HES1) is one of the notch signaling target genes which is a basic helix-loop-helix (bHLH) transcription factor acting as a proliferation stimulator through the suppression of cell cycle inhibitors such as p27 and p21.. In this study, we aimed to analyze the role of HES1 in the progression of esophageal squamous cell carcinoma (ESCC).. Messenger RNA (mRNA) expression of HES1 in fresh tumoral tissues and their margin normal samples were assessed in 50 ESCC patients by real-time polymerase chain reaction (RT-PCR).. Thirteen out of 50 cases (26 %) had HES1 underexpression, while HES1 overexpression was observed only in 4 (8 %) samples. HES1 underexpression was significantly correlated with tumor depth of invasion (P = 0.035).. Although we have not observed any significant correlation between the HES1 expression and notch activation in ESCC, this study is the first report that elucidated the HES1 underexpression in ESCC and revealed its correlation with the invasiveness of ESCC.

Topics: Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Homeodomain Proteins; Humans; Male; Middle Aged; Prognosis; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factor HES-1