BACKGROUND: DEAD-box RNA helicase 19 A (DDX19A) is overexpressed in cervical squamous cell carcinoma. However, its role in gastric cancer remains unclear. The present study aimed to explore the role and underlying mechanism of DDX19A in the development of gastric cancer.
METHODS: The expression of DDX19A in gastric cancer and paracancerous tissues was evaluated through quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The biological functions of DDX19A in gastric cancer were determined using CCK8, plate colony-forming, and Transwell migration assays. The specific mechanism of DDX19A in gastric cancer cells was studied using western blotting, RNA-binding protein immunoprecipitation, mRNA half-life detection, and nuclear and cytoplasmic RNA isolation.
RESULTS: DDX19A was highly expressed in gastric cancer and positively associated with malignant clinicopathological features and poor prognosis. Additionally, DDX19A promoted gastric cancer cell proliferation, migration, and epithelial-mesenchymal transition phenotypes. Mechanistically, DDX19A activated the PI3K/AKT pathway by upregulating phosphatidylinositol-3-kinase (PIK3CA) expression. Furthermore, DDX19A interacted with PIK3CA mRNA, stabilized it, and facilitated its export from the nucleus.
CONCLUSIONS: Our study reveals a novel mechanism whereby DDX19A promotes the proliferation and migration of gastric cancer cells by enhancing the stability and nuclear export of PIK3CA mRNA, thereby activating the PI3K/AKT pathway.

UNASSIGNED: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are associated with drug resistance and prognosis in lung cancer; however, the consistency and clinical value of PIK3CA mutations between tissue and liquid samples are unknown.
UNASSIGNED: Circulating tumor DNA (ctDNA) and matched tumor tissue samples from 405 advanced lung cancer patients were collected at Jilin Cancer Hospital between 2018 and 2022, and the PIK3CA mutation status was sequenced using next-generation sequencing based on a 520 gene panel. The viability of different mutant lung cancer cells was detected using MTT assay.
UNASSIGNED: PIK3CA mutations were detected in 46 (5.68 %) of 810 lung cancer samples, with 21 (5.19 %) of 405 plasma samples and 25 (6.17 %) of 405 matched tissues. p.Glu542Lys, p.Glu545Lys, and p.His1047Arg were the most common mutation types of PIK3CA in both the ctDNA and tissue samples. The concordance of PIK3CA mutations was 97.53 % between ctDNA and matched tissues (kappa: 0.770, P = 0.000), with sensitivity/true positive rate of 72.0 %, specificity/true negative rate of 99.2 %, and negative predictive value and positive predictive value of 0.982 and 0.857, respectively (AUC = 0.856, P = 0.000). Furthermore, the concordance of PIK3CA mutations was 98.26 % in lung adenocarcinoma and 96.43 % in lung squamous cell carcinoma. TP53 and EGFR were the most common concomitant mutations in ctDNA and tissues. Patients with PIK3CA mutations showed a high tumor mutational burden (TMB) (P < 0.001) and a significant correlation between bTMB and tTMB (r = 0.5986, P = 0.0041). For the tPIK3CAmut/ctDNA PIK3CAmut cohort, PI3K pathways alteration was associated with male sex (P = 0.022), old age (P = 0.007), and smoking (P = 0.001); tPIK3CAmut/ctDNA PIK3CAwt patients harbored clinicopathological factors of adenocarcinoma stage IV, with low PS score (≤1) and TMB.
UNASSIGNED: This study showed that ctDNA is highly concordant and sensitive for identifying PIK3CA mutations, suggesting that PIK3CA mutation detection in liquid samples may be an alternative clinical practice for tissues.

UNASSIGNED: Mesenchymal stem cells can develop into osteoblasts, making them a promising cell-based osteoporosis treatment. Despite their therapeutic potential, their molecular processes are little known. Bioinformatics and experimental analysis were used to determine the molecular processes of bone marrow mesenchymal stem cell (BMSC) therapy for postmenopausal osteoporosis (PMO).
UNASSIGNED: We used weighted gene co-expression network analysis (WGCNA) to isolate core gene sets from two GEO microarray datasets (GSE7158 and GSE56815). GeneCards found PMO-related genes. GO, KEGG, Lasso regression, and ROC curve analysis refined our candidate genes. Using the GSE105145 dataset, we evaluated KLF2 expression in BMSCs and examined the link between KLF2 and PIK3CA using Pearson correlation analysis. We created a protein-protein interaction network of essential genes involved in osteoblast differentiation and validated the functional roles of KLF2 and PIK3CA in BMSC osteoblast differentiation in vitro.
UNASSIGNED: We created 6 co-expression modules from 10 419 differentially expressed genes (DEGs). PIK3CA, the key gene in the PI3K-Akt pathway, was among 197 PMO-associated DEGs. KLF2 also induced PIK3CA transcription in PMO. BMSCs also expressed elevated KLF2. BMSC osteoblast differentiation involved the PI3K-Akt pathway. In vitro, KLF2 increased PIK3CA transcription and activated the PI3K-Akt pathway to differentiate BMSCs into osteoblasts.
UNASSIGNED: BMSCs release KLF2, which stimulates the PIK3CA-dependent PI3K-Akt pathway to treat PMO. Our findings illuminates the involvement of KLF2 and the PI3K-Akt pathway in BMSC osteoblast development, which may lead to better PMO treatments.

Palmoplantar keratoderma (PPK) is a group of -disorders with genetic and phenotypic heterogeneity featuring skin thickening of the palms and soles. More than 60 genes involved in various biological processes are implicated in PPK. PIK3CA is an oncogene encoding p110α, and its somatic variants contribute to a spectrum of congenital overgrowth disorders, including epidermal nevi (EN). To identify the genetic basis and elucidate the pathogenesis of a patient with unilateral focal PPK. Whole-exome sequencing and Sanger sequencing combined with laser capture microdissection (LCM) were performed on genomic DNA extracted from the patient\'s peripheral blood and skin lesion. Skin biopsies were taken from the lesion of the patient and normal controls for immunofluorescence. Molecular docking was performed using Alphafold2-multimer. A three-year-old girl presented with unilateral focal PPK with an identified missense -variant (c.3140A>G, p.His1047Arg) in PIK3CA from affected tissue. This variant only existed in the lesional epidermis. Elevated PI3K/AKT/mTOR signalling in the affected epidermis and an increased number of Ki67-positive keratinocytes were demonstrated. Molecular docking indicated instability of the p110α-p85α dimer caused by the PIK3CA His1047Arg variant. We describe the first PPK case associated with a variant in PIK3CA, which expands the spectrum of PIK3CA-related disorders. Our study further underscores the importance of the PI3K/AKT/mTOR pathway in the homeostasis of skin keratinization.

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies and the development of new drugs is crucial for the treatment of this lethal disease. Iheyamine A is a nonmonoterpenoid azepinoindole alkaloid from the ascidian Polycitorella sp., and its anticancer mechanism has not been investigated in leukemias. Herein, we showed the significant antileukemic activity of L42 in AML cell lines HEL, HL-60 and THP-1. The IC50 values were 0.466±0.099 µM, 0.356±0.023 µM, 0.475±0.084 µM in the HEL, HL-60 and THP-1 cell lines, respectively, which were lower than the IC50 (2.594±0.271 µM) in the normal liver cell line HL-7702. Furthermore, L42 significantly inhibited the growth of peripheral blood mononuclear cells (PBMCs) from an AML patient. In vivo, L42 effectively suppressed leukemia progression in a mouse model induced by Friend murine leukemia virus (F-MuLV). Mechanistically, we showed that L42 induced cell cycle arrest and apoptosis in leukemia cell lines. RNA sequencing analysis of L42-treated THP-1 cells revealed that the differentially expressed genes (DEGs) were enriched in the cell cycle and apoptosis and predominantly enriched in the PI3K/AKT pathway. Accordingly, L42 decreased the expression of the phospho-PI3K (p85), phospho-AKT and phospho-FOXO3a. Docking and CETSA analysis indicated that L42 bound to the PI3K isoform p110α (PIK3CA), which was implicated in the suppression of the PI3K/AKT pathway. L42 was also shown to initiate the TNF signaling-mediated apoptosis. Moreover, L42 exhibited stronger anti-leukemia activity and sensitivity in IDH2-mutant HEL cells than in IDH2-wild-type control. In conclusion, L42 effectively suppresses cell proliferation and triggers apoptosis in AML cell lines in part through inhibition of the PI3K/AKT signaling pathway to restore FOXO3a expression and activation of the TNF signaling pathway. Thus, the iheyamine A derivative L42 represents a novel candidate for AML therapy.

The aggressive characteristics of triple-negative breast cancer (TNBC) and the absence of targeted medicines make TNBC a challenging clinical case. The molecular landscape of TNBC has been well-understood thanks to recent developments in multi-omic analysis, which have also revealed dysregulated pathways and possible treatment targets. This review summarizes the utilization of multi-omic approaches in elucidating TNBC\'s complex biology and therapeutic avenues. Dysregulated pathways including cell cycle progression, immunological modulation, and DNA damage response have been uncovered in TNBC by multi-omic investigations that integrate genomes, transcriptomics, proteomics, and metabolomics data. Methods like this pave the door for the discovery of new therapeutic targets, such as the EGFR, PARP, and mTOR pathways, which in turn direct the creation of more precise treatments. Recent developments in TNBC treatment strategies, including immunotherapy, PARP inhibitors, and antibody-drug conjugates, show promise in clinical trials. Emerging biomarkers like MUC1, YB-1, and immune-related markers offer insights into personalized treatment approaches and prognosis prediction. Despite the strengths of multi-omic analysis in offering a more comprehensive view and personalized treatment strategies, challenges exist. Large sample sizes and ensuring high-quality data remain crucial for reliable findings. Multi-omic analysis has revolutionized TNBC research, shedding light on dysregulated pathways, potential targets, and emerging biomarkers. Continued research efforts are imperative to translate these insights into improved outcomes for TNBC patients.

OBJECTIVE: Our aim was to compare the PIK3CA mutation status in matched primary and recurrent tumors of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (BC) to gain insight into the optimization of patient selection and detection time for PIK3CA-targeted therapy.
METHODS: The data were from 3035 patients with BC diagnosed at the Breast Disease Center, Peking University First Hospital, between January 2008 and December 2017. Matched primary and recurrent samples were profiled using amplification-refractory mutation system-polymerase chain reaction covering 11 mutational hotspots in PIK3CA.
RESULTS: PIK3CA mutations were detected in 54.3% primary tumors and 48.6% corresponding recurrences. PIK3CA mutation was detected in 37.5% cases in the locoregional recurrent group and 40.0% of distant metastasis, without a statistical difference. Besides, PIK3CA mutations were concordant in 88.6% of the matched pairs. For patients treated with neoadjuvant chemotherapy, 100% concordance was observed. However, PIK3CA mutation was neither correlated with clinicopathological features nor associated with clinical outcomes.
CONCLUSIONS: Mutations in PIK3CA in HR+/HER2- BC generally progressed to recurrent tumors. The high concordance rate of PIK3CA mutation status between primary tumors and corresponding recurrences suggests that the detection of primary tumors could be a substitute approach when recurrent samples are not easily obtainable.

UNASSIGNED: Although LncRNA JPX has been linked to a number of malignancies, it is yet unknown how it relates to endometrial carcinoma (EC). Investigating the expression, functional activities, and underlying molecular processes of lncRNA JPX in EC was the goal of this work.
UNASSIGNED: RT-qPCR was used to examine the differences in lncRNA/microRNA (miRNA, miR)/mRNA expression between normal cervical and EC tissues or cells. Cell Counting Kit-8, flow cytometry, and transwell were used to evaluate the association between lncRNA JPX/miR-140-3p/phosphoinositide-3-kinase catalytic subunit α (PIK3CA) in Ishikawa and JEC cell lines. The impact of JPX on the downstream janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway was investigated using Western blot analysis.
UNASSIGNED: When comparing EC tissues to nearby normal tissues, JPX expression is markedly increased in EC tissues, with greater expression in advanced-stage EC. Furthermore, compared to normal epithelial cells, EC cell lines have higher levels of JPX expression. In Ishikawa and JEC endometrial cancer cell lines, we used siRNA-mediated suppression of JPX to find lower cell viability, increased apoptosis, cell cycle arrest, and reduced migration and invasion. We next verified that miR-140-3p binds to downstream target cells to impede the transcription and translation of PIK3CA, which in turn prevents the growth of Ishikawa and JEC cells. JPX functions as a ceRNA to adsorb miR-140-3p. This procedure required controlling JAK2/STAT3, a downstream signal.
UNASSIGNED: JPX enhances the development of Ishikawa and JEC cells and activates downstream JAK2/STAT3 signal transduction via the miR-140-3p/PIK3CA axis, offering a possible therapeutic target for the treatment of EC.

BACKGROUND: The status of the lung adenocarcinoma (LUAD) grading system and the association between LUAD differentiation, driver genes, and clinicopathological features remain to be elucidated.
METHODS: We included patients with invasive non-mucinous LUAD, evaluated their differentiation, and collected available clinicopathological information, gene mutations, and analyzed clinical outcomes.
RESULTS: Among the 907 patients with invasive non-mucinous LUAD, 321 (35.4 %) were poorly differentiated, 422 (46.5 %) were moderately differentiated, and 164 (18.1 %) were well differentiated. EGFR mutation was more common in the LUADs accompanied without CGP (complex glandular pattern) than LUADs with CGP (p < 0.001). Correlation analysis between mutations and clinical characteristics showed that EGFR gene mutation (p < 0.001), KRAS gene mutation (p < 0.05), and ALK gene rearrangement (p < 0.001) were significantly related to the degree of tumor differentiation, and the KRAS and ALK gene mutation frequencies were higher in the low-differentiation group than in the high and medium differentiation groups. The EGFR mutation frequency was higher in the well/moderately differentiated adenocarcinoma group.
CONCLUSIONS: Our study adds to the evidence regarding the role of the grading system in prognosis. EGFR, KRAS, and ALK are related to the degree of tumor differentiation.

BACKGROUND: Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported.
METHODS: In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.
RESULTS: Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2-year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12-month progression-free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2-55.6), with an 18-month PFS rate of 37.8% (95% CI, 22.7-52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3-36.9), and the 24-month OS rate was 47.8% (95% CI, 31.7-62.3). Age > 50 years, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study.
CONCLUSIONS: Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy. No new safety signals were noted with long-term treatment.