hes1-protein--human and Precancerous-Conditions

Cervical cancer (CC) is the most common cancer affecting women worldwide. Human papillomavirus (HPV) infection is a major contributing factor for the development of CC. The development of CC occurs progressively from precancer stages to cancerous stages (ie, invasive squamous cell carcinoma [ISCC] and adenocarcinoma [ADC]). ADC is a rare form of CC that develops from the mucinous endocervical epithelium. It is believed that the downstream targets of Notch signaling contribute to the etiology of CC. One such target is HES1, whose role in the modulation of ADC is unknown. The purpose of this study is to determine the role of HES1 protein in HPV-associated ADC subtype of CC and also to compare its expression in histologic subtypes of precancer and ISCC.. A total of 148 patients (30 with precancers, 98 with ISCC, and 20 with ADC) and 40 normal control participants were analyzed for the expression of HES1 via immunohistochemistry, with results validated by immunoblotting.. The comparison between HPV-16 and HES1 expression was significant in precancer (cervical intraepithelial neoplasia grades 1 to 3; P = .013), ISCC (International Federation of Gynecology and Obstetrics stages I to IV; P = .001), and ADC ( P = .007). An overall significant mean difference was observed between HES1, JAG1, and Notch-3 proteins in precancer ( P = .001), ISCC ( P = .001), and ADC ( P = .001). Pairwise comparisons between HES1 and JAG1 and HES1 and Notch-3 were also found to be significant.. This study showed that among all HPV-16-positive precancers, the major HES1 positivity signal arises from cervical intraepithelial neoplasia grades 2 and 3 that develops into ISCC. Moreover, HPV-16-positive ADC also showed an association with HES1. The HES1, JAG1, and Notch-3 proteins showed their synergistic role in modulating HPV associated ADC along with histologic subtypes of precancer and ISCC of CC.

Topics: Carcinoma, Squamous Cell; Case-Control Studies; Female; Humans; Immunohistochemistry; Neoplasm Staging; Papillomaviridae; Papillomavirus Infections; Precancerous Conditions; Receptor, Notch3; ROC Curve; Transcription Factor HES-1; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Notch pathway molecules crosstalk with Wnt/β-catenin signaling cascade in stem cells and tumors. However, the correlation between the expression pattern of Notch intracellular domain NICD, Hes-1 and c-Myc has not been studied in oral squamous cell carcinoma. The aim of this study is to investigate the correlation and prognostic significance of NICD, Hes-1 and c-Myc in oral cancer. Immunohistochemistry was used to study the expression pattern of NICD, Hes-1 and c-Myc in oral preneoplastic and neoplastic tissues. In addition, double immunofluorescence was used to examine the co-localization of NICD, Hes-1 and c-Myc in H314 cells. The expression pattern of NICD and Hes-1 was gradually increased from normal to dysplasia to carcinoma. Interestingly, statistically significant correlation was not observed between NICD, Hes-1 and c-Myc in oral squamous cell carcinoma. Furthermore, NICD+/c-Myc+ and Hes-1+/c-Myc+ double positive cases showed worst survival when compared with other cases in oral cancer. Notch signaling molecules, NICD and Hes-1, are found to be involved in the progression of oral squamous cell carcinoma. Interestingly, NICD, Hes-1 and c-Myc may have independent roles in oral cancer. On the other hand, we have demonstrated that NICD+/c-Myc+ and Hes-1+/c-Myc+ double positivity might be used as independent prognostic indicator of oral carcinoma.

Topics: Aged; Basic Helix-Loop-Helix Transcription Factors; Epithelium; Female; Homeodomain Proteins; Humans; Male; Middle Aged; Mouth Neoplasms; Nestin; Precancerous Conditions; Protein Structure, Tertiary; Proto-Oncogene Proteins c-myc; Receptors, Notch; Reference Values; Survival Analysis; Transcription Factor HES-1

The biologic effects of Notch1 and Notch2 vary with cancer types and their potential role(s) in gastric cancers (GCs) remains largely unknown.. This study aimed to address the previously mentioned issue by checking the expression of Notch1, Notch2, and Notch target gene Hes1 in GCs, premalignant gastric lesions, and noncancerous endoscopic gastric mucosa and by inhibiting Notch signal transduction in GC cells.. The status of Notch1, Notch2, and Hes1 expression in 74 GC surgical specimens, 10 endoscopic samples, and 4 human GC cell lines was evaluated by tissue microarray-based immunohistochemical staining, Western blotting, and reverse transcription-polymerase chain reaction, and the importance of Notch signaling was elucidated by treating 2 GC cell lines with 2 γ-secretase inhibitors.. Notch1 was undetectable in noncancerous gastric mucosa but was expressed with nuclear translocation in 16.7% (4 of 24) of chronic gastritis, 50.0% (9 of 18) of intestinal metaplasia, 54.2% (26 of 48) of intestinal GC, and 23.1% (6 of 26) of diffuse GC, showing distinct differences of Notch1 detection rates between either intestinal metaplasia and chronic gastritis or intestinal GCs and diffuse GCs (P  =  .03; P  =  .005, respectively). Notch2 nuclear translocation frequencies were 10.0% (1 of 10) in noncancerous endoscopic mucosa, 71.4% (30 of 42) in premalignant lesions, and 97.3% (72 of 74) in GC tissues, demonstrating a correlation of Notch2 expression with both intestinal GC and diffuse GC formation (P < .001). The rates of nuclear-Hes1 labeling were 1 of 10 among noncancerous, 42.9% premalignant, and 81.1% cancer tissues, which were closely correlated with Notch2 (P < .001) rather than Notch1 (P  =  .42) nuclear translocation. Only Notch2 was expressed accompanied with Hes1 nuclear labeling in the 4 GC cell lines established from diffuse GC cases. Inhibition of Notch signaling with γ-secretase inhibitors, L-685,458 and DAPT, prevented Hes1 nuclear translocation but neither suppressed growth nor induced cell death.. This study demonstrated a close correlation of Notch2 expression with GC formation and the potential link of Notch1 upregulation with intestinal-like phenotypes of gastric lesions. Although inhibition of Notch activity failed to achieve anti-GC effects, the activated Notch signaling may reflect a potential GC risk.

Topics: Adenocarcinoma; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Gastrectomy; Gastric Mucosa; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Precancerous Conditions; Receptor, Notch1; Receptor, Notch2; RNA, Messenger; Signal Transduction; Stomach Neoplasms; Tissue Array Analysis; Transcription Factor HES-1