Deciphering STAT3's negative regulation of LHPP in ESCC progression through single-cell transcriptomics analysis.

BACKGROUND: Esophageal Squamous Cell Carcinoma (ESCC) remains a predominant health concern in the world, characterized by high prevalence and mortality rates. Advances in single-cell transcriptomics have revolutionized cancer research by enabling a precise dissection of cellular and molecular diversity within tumors. OBJECTIVE: This study aims to elucidate the cellular dynamics and molecular mechanisms in ESCC, focusing on the transcriptional influence of STAT3 (Signal Transducer and Activator of Transcription 3) and its interaction with LHPP, thereby uncovering potential therapeutic targets. METHODS: Single-cell RNA sequencing was employed to analyze 44,206 cells from tumor and adjacent normal tissues of ESCC patients, identifying distinct cell types and their transcriptional shifts. We conducted differential gene expression analysis to assess changes within the tumor microenvironment (TME). Validation of key regulatory interactions was performed using qPCR in a cohort of 21 ESCC patients and further substantiated through experimental assays in ESCC cell lines. RESULTS: The study revealed critical alterations in cell composition and gene expression across identified cell populations, with a notable shift towards pro-tumorigenic states. A significant regulatory influence of STAT3 on LHPP was discovered, establishing a novel aspect of ESCC pathogenesis. Elevated levels of STAT3 and suppressed LHPP expression were validated in clinical samples. Functional assays confirmed that STAT3 directly represses LHPP at the promoter level, and disruption of this interaction by promoter mutations diminished STAT3's repressive effect. CONCLUSION: This investigation underscores the central role of STAT3 as a regulator in ESCC, directly impacting LHPP expression and suggesting a regulatory loop crucial for tumor behavior. The insights gained from our comprehensive cellular and molecular analysis offer a deeper understanding of the dynamics within the ESCC microenvironment. These findings pave the way for targeted therapeutic interventions focusing on the STAT3-LHPP axis, providing a strategic approach to improve ESCC management and prognosis.

An updated review of immunotherapy in esophageal cancer: PD-L1 footprint.

Esophageal cancer is considered one of the most significant challenges to public health worldwide. While various therapeutic options exist for esophageal cancer, including chemotherapy, radiotherapy, and surgery, several adverse effects of these medications have been reported. Therefore, a new generation of therapeutic lines should be applied to minimize complications. In this regard, immunotherapy is a novel approach that aims to kill tumor cells directly by targeting them. Specifically, monoclonal antibodies can target specific markers of esophageal cancer tumor cells, keeping other normal cells safe. Multiple monoclonal antibodies optimized for esophageal cancer, such as pembrolizumab, ramucirumab, trastuzumab, nivolumab, and ipilimumab, are available. On the other hand, esophageal cancer tumor cells express a specific inhibitory ligand and its receptor called programmed cell death, which can suppress T cell immune responses. This receptor provides an inhibitory signal, causing the highest expression of the PD-L1 ligand on tumor cells. The outcomes of this interaction lead to the suppression of the activation and function of T lymphocytes. Therefore, immunotherapy for esophageal cancer targeting the PD-1/PD-L1 pathway has shown a remarkable correlation with cancer care. This study presents a comprehensive review of the latest findings related to immunotherapy in esophageal cancer.

Long non-coding RNA SRA1 suppresses radiotherapy resistance in esophageal squamous cell carcinoma by modulating glycolytic reprogramming.

Esophageal squamous cell carcinoma (ESCC), a highly aggressive subtype of esophageal cancer, is characterized by late-stage diagnosis and limited treatment options. Recent advancements in transcriptome sequencing technologies have illuminated the molecular intricacies of ESCC tumors, revealing metabolic reprogramming as a prominent feature. Specifically, the Warburg effect, marked by enhanced glycolysis, has emerged as a hallmark of cancer, offering potential therapeutic targets. In this study, we comprehensively analyzed bulk RNA-seq data from ESCC patients, uncovering elevated SRA1 expression in ESCC development and a poorer prognosis. Silencing of SRA1 led to a modulation of glycolysis-related products and a shift in PKM2 expression. Our findings shed light on the intricate molecular landscape of ESCC, highlighting SRA1 as a potential therapeutic target to disrupt glycolysis-dependent energy production. This metabolic reprogramming may hold the key to innovative treatment strategies for ESCC, ultimately improving patient outcomes.

Long noncoding RNA steroid receptor RNA activator 1 inhibits proliferation and glycolysis of esophageal squamous cell carcinoma.

BACKGROUND: The clinical effects and detailed roles of long non-coding RNA (LncRNA) steroid receptor RNA activator 1 (SRA1) in esophageal squamous cell carcinoma (ESCC) remain ambiguous. In the present study, the complementary sites between lncRNA SRA1, miRNA-363-5p, and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) predicted via bioinformatics analysis stimulated us to hypothesize that miRNA-363-5p/LHPP axis might be required for SRA1-mediated ESCC progression. AIM: To investigate the molecular events of SRA1 in the malignant behavior in ESCC. METHODS: Thirty-eight ESCC tissues and paired adjacent normal tissues were acquired. SRA1 expression was detected in ESCC tissues and cell lines using quantitative reverse transcription-polymerase chain reaction. Cell counting Kit-8 assay, transwell invasion assay, glycolysis assay, and xenograft tumor model were performed to address the malignant biological behaviors of ESCC cells after the introduction of SRA1. The t-test and the χ 2 test were used for comparison between groups. Survival curve analysis was performed using the Kaplan-Meier method. RESULTS: SRA1 downregulation was identified in ESCC. ESCC patients exhibiting a low SRA1 expression faced shorter overall survival than those with a high SRA1 expression. The introduction of SRA1 inhibited cell proliferation, glucose uptake, and lactate production in ESCC. In vivo, the growth of ESCC was hindered by SRA1 overexpression. Then, SRA1 overexpresses the LHPP by inhibiting miRNA-363-5p. Lastly, the introduction of small interfering RNA si-LHPP or miRNA-363-5p mimic could abrogate the inhibition roles triggered by SRA1. CONCLUSION: SRA1 inhibits the oncogenicity of ESCC via miRNA-363-5p/LHPP axis. The SRA1/miRNA-363-5p/LHPP pathway may be a therapeutic target for ESCC.

Identification of Tumor Suppressor Gene LHPP-Based 5-microRNA Signature That Predicts the Early- and Midstage Esophageal Squamous Cell Carcinoma: A Two-Stage Case-Control Study in the Chinese Han Population.

OBJECTIVE: To establish a novel approach for diagnosing early- and midstage esophageal squamous cell carcinoma (ESCC). METHODS: The tumor suppressor gene phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP)-based miRNA signature was identified using next-generation sequencing and 3 biological online prediction systems. This retrospective study established and validated an ESCC prediction model using a test cohort and a validation cohort. RESULTS: Immunohistochemical staining and real-time quantitative polymerase chain reaction (RT-qPCR) results showed that LHPP protein levels were significantly lower in tissues with early- and midstage ESCC than in adjacent tissues (P < .01). Further, we confirmed that miR-15b-5p, miR-424-5p, miR-497-5p, miR-363-5p, and miR-195-5p inhibited LHPP. These 5 miRNAs were significantly elevated in the plasma of early- and midstage ESCC (P < .05). An ESCC prediction model combining these 5 miRNAs was established. Finally, in the external validation cohort, the model exhibited high discriminative value (sensitivity/specificity: 84.4%/93.3%). CONCLUSIONS: The prediction model has potential implications for diagnosis of early- and midstage ESCC.

[Effects of different compositions of Gegenqinlian decoction on experimental shigellosis in rabbits].

OBJECTIVE: To investigate the relations between different compositions of Gegenqinlian decoction and their effects on experimental shigellosis in rabbits to explore the composition protocol of Gegenqinlian decoction. METHODS: Rabbit models of intestinal invasion induced by Shigella flexneri was established by directly inoculating the bacterium in the colon after cecum bypass operation. The effects of different compositions of Gegenqinlian decoction on the indexes of colitis and the bacterial count of Shigella in the colon content and colon tissue were investigated by orthogonal design. RESULTS: According to the bacterial count of Shigella in the colon, Coptis chinensis franch and Scutellaria baicalensis Georgi are the main effective drugs, but they antagonized each other, so that the best combination protocol was Coptis chinensis Franch only. CONCLUSION: Among the components of Gegenqinlian decoction, Coptis chinensis franch has the strongest pharmacological effect against bacteria and Glycyrrhina wralensis fisch is the most effective to ameliorate pathological lesions.