The v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene is one of the most critical proto-oncogenes and functions as a key regulator in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. The incidence of BRAF mutations in non-small cell lung cancer (NSCLC) patients ranges from 1.5% to 5.5%, with BRAF V600 mutations accounting for approximately 30%-50% of all BRAF mutations, among which BRAF V600E represents the most prevalent mutation type. Currently, the combination of Dabrafenib and Trametinib has been recommended as first-line therapy for BRAF V600-mutant NSCLC by multiple domestic and international guidelines including National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and Chinese Society of Clinical Oncology (CSCO). However, there are no clear targeted treatment recommendations for BRAF non-V600 mutations. Although case reports suggest that Dabrafenib combined with Trametinib may be effective for patients with BRAF non-V600 mutations, the efficacy and safety require further validation due to limited sample size and lack of large-scale clinical trial data. This article reports a case of NSCLC with a rare BRAF insertion and deletion mutation that responded well to the treatment of Dabrafenib in combination with Trametinib, aiming to enhance clinicians' understanding of such NSCLC cases with extremely rare mutation and provide a reference for future treatment strategies.
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Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Imidazoles/administration & dosage* ; Lung Neoplasms/pathology* ; Mutation ; Neoplasm Metastasis ; Oximes/administration & dosage* ; Proto-Oncogene Mas ; Proto-Oncogene Proteins B-raf/genetics* ; Pyridones/administration & dosage* ; Pyrimidinones/administration & dosage*

OBJECTIVE: Tumor-derived exosomes (TDEs) play crucial roles in intercellular communication. Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis. Jiedu recipe (JR), a traditional Chinese medicinal formula, has demonstrated efficacy in preventing the metastasis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unknown. METHODS: Animal experiments were performed to investigate the metastasis-preventing effects of JR. Bioinformatics analysis and in vitro assays were conducted to explore the potential targets and active components of JR. TDEs were assessed using nanoparticle tracking analysis (NTA) and Western blotting (WB). Exosomes derived from normoxic or hypoxic HCC cells (H-TDEs) were collected to establish premetastatic mouse models. JR was intragastrically administered to evaluate its metastasis-preventive effects. WB and lysosomal staining were performed to investigate the effects of JR on lysosomal function and autophagy. Bioinformatics analysis, WB, NTA, and immunofluorescence staining were used to identify the active components and potential targets of JR. RESULTS: JR effectively inhibited subcutaneous-tumor-promoted lung premetastatic niche development and tumor metastasis. It inhibited the release of exosomes from tumor cells under hypoxic condition. JR treatment promoted both lysosomal acidification and suppressed secretory autophagy, which were dysregulated in hypoxic tumor cells. Quercetin was identified as the active component in JR, and the epidermal growth factor receptor (EGFR) was identified as a potential target. Quercetin inhibited EGFR phosphorylation and promoted the nuclear translocation of transcription factor EB (TFEB). Hypoxia-impaired lysosomal function was restored, and secretory autophagy was alleviated by quercetin treatment. CONCLUSION JR suppressed HCC metastasis by inhibiting hypoxia-stimulated exosome release, restoring lysosomal function, and suppressing secretory autophagy. Quercetin acted as a key component of JR and regulated TDE release through EGFR-TFEB signaling. Our study provides a potential strategy for retarding tumor metastasis by targeting H-TDE secretion. Please cite this article as: Jia WT, Xiang S, Zhang JB, Yuan JY, Wang YQ, Liang SF, Lin WF, Zhai XF, Shang Y, Ling CQ, Cheng BB. Jiedu recipe, a compound Chinese herbal medicine, suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment through the EGFR-TFEB signaling pathway. J Integr Med. 2024; 22(6): 697-709.
Exosomes/drug effects* ; Animals ; Carcinoma, Hepatocellular/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Liver Neoplasms/pathology* ; Tumor Microenvironment/drug effects* ; Mice ; Humans ; Cell Line, Tumor ; Mice, Inbred BALB C ; Neoplasm Metastasis ; Male ; Mice, Nude

Humans ; MicroRNAs/genetics* ; Cell Line, Tumor ; Osteosarcoma/pathology* ; Neoplasm Invasiveness ; Cell Proliferation ; Bone Neoplasms/pathology* ; Cell Movement ; Neoplasm Metastasis

OBJECTIVE: To analyze the correlation between the mRNA levels of breast cancer resistance protein (BCRP) and lung-specific X protein (LUNX) genes with pathological types and stages of patients with non-small cell lung cancer (NSCLC) and their significance for prognosis. METHODS: Eighty nine patients with NSCLC admitted to Huaihe Hospital of Henan University between June 2015 and June 2018 were recruited, with 55 patients with benign lung lesions admitted during the same period of time selected as the control group. The mRNA levels of BCRP and LUNX genes were detected in the peripheral blood samples from the two groups, and their correlation with the clinicopathological characteristics and prognosis of the patients was analyzed. RESULTS: The expression rates of BCRP and LUNX mRNA in the NSCLC group were significantly higher compared with the control group (P < 0.05). The level of BCRP mRNA of the NSCLC patients has correlated with the degree of differentiation and TNM staging (P < 0.05), but not with gender, age, smoking, pathological types and lymph node metastasis (P > 0.05). The level of LUNX mRNA of them has correlated with the degree of differentiation, TNM staging and lymph node metastasis (P < 0.05), but not with gender, age, smoking, and pathological types (P > 0.05). Compared with those with no expression, the overall survival rate of patients with BCRP and LUNX expression was significantly lower (P < 0.05). The degree of differentiation, TNM staging, lymph node metastasis, and expression of the BCRP and LUNX mRNA may all affect the prognosis of the patients. CONCLUSION The levels of BCRP and LUNX mRNA in the peripheral blood of patients with NSCLC are significantly increased. The expression of BCRP mRNA is correlated with the degree of differentiation and TNM staging, whilst the expression of LUNX mRNA is correlated with the differentiation degree, TNM staging and lymph node metastasis. Both may be used as independent predictors for the prognosis of patients with NSCLC.
Humans ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Biomarkers, Tumor/genetics* ; Carcinoma, Non-Small-Cell Lung/pathology* ; Glycoproteins/genetics* ; Lung Neoplasms/pathology* ; Lymphatic Metastasis ; Neoplasm Proteins/genetics* ; Phosphoproteins/genetics* ; Prognosis ; RNA, Messenger/genetics*

OBJECTIVE: To investigate the regulatory effect of miR-4324 on ankyrin 2(Talin2) expression and biological behaviors of breast cancer cells and the clinical implications of changes in miR-4324 and Talin2 expressions in breast cancer. METHODS: In breast cancer and adjacent tissues, the expressions of Talin2 and miR-4324 were examined with immunohistochemistry and qRT-PCR, respectively and the association of Talin2 expression levels with the prognosis and clinicopathological features of breast cancer patients was analyzed.The human breast cancer cell line SKBR-3 was transfected with miR-4324 mimic, miR-4324 inhibitor, si-Talin2, or both miR-4324 inhibitor and si-Talin2, and the changes in biological behaviors of the cells were examined; the cellular expression of Talin2at the mRNA and protein levels were detected with qRT-PCR and Western blotting.Dual luciferase reporter gene assay was used to verify the targeting relationship between miR-4324 and Talin2.The effect of miR-4324-mediated regulation of Talin2 on SKBR-3 cell migration was assessed using Transwell assays. RESULTS: Talin2 expression was significantly higher in breast cancer tissues than in the adjacent tissues, and its expression level was correlated with lymph node metastasis and high HER-2 expression in breast cancer (P < 0.05) but not with the patient's age, clinical stage, histological grade or expressions of estrogen and progesterone receptors (P >0.05).The expression of miR-4324 was significantly reduced in breast cancer tissues as compared with the adjacent tissues (P < 0.01).In SKBR-3 cells, transfection with miR-4324 mimics significantly inhibited proliferation, migration and invasion (P < 0.05) and promoted apoptosis (P < 0.01) of the cells.Dual luciferase reporter gene assay confirmed that cotransfection with miR-4324 mimics significantly reduced luciferase activity of Talin2-3'-UTR WT reporter plasmid (P < 0.05).Transfection of the cells with miR-4324 mimics significantly reduced mRNA and protein expressions of Talin2(P < 0.05).Transwell migration assay showed that the migration ability of SKBR-3 cells was significantly enhanced after transfection with miR-4324 inhibitor (P < 0.01), lowered after transfection with si-Talin2(P < 0.01), and maintained at the intermediate level after co-transfection with miR-4324 inhibitor+si-Talin2 group (P < 0.05). CONCLUSIONS High expression of Talin2 is associated with lymph node metastasis and HER-2 overexpression in breast cancer patients.Down-regulation of miR-4324 inhibits the proliferation, invasion and migration and induces apoptosis of breast cancer cells, and the inhibitory effect of miR-4324 knockdown on breast cancer cell migration is mediated probably by targeted inhibition of Talin2 expression.
Female ; Humans ; Breast Neoplasms/pathology* ; Cell Line, Tumor ; Cell Movement/genetics* ; Cell Proliferation/genetics* ; Gene Expression Regulation, Neoplastic ; Luciferases/genetics* ; Lymphatic Metastasis ; MicroRNAs/metabolism* ; Neoplasm Invasiveness/genetics* ; RNA, Messenger

Antiporters/genetics* ; Carcinoma, Papillary/pathology* ; Humans ; Neoplasm Metastasis/genetics* ; Sulfate Transporters/genetics* ; Thyroid Cancer, Papillary/pathology* ; Thyroid Neoplasms/pathology*

OBJECTIVE: To analyze the correlation of methylation status of dachshund homolog 1 (DACH1) gene in tumor tissues with clinicopathological characteristics and prognosis of patients of esophageal cancer. METHODS: Tumor tissue, paracancerous tissue and normal esophageal mucosal specimens of 104 patients with esophageal cancer were collected. Methylation-specific PCR was used to determine the methylation status of the DACH1 gene. Univariate analysis and multivariate Logistic regression model were used to analyze the correlation between DACH1 methylation status and clinical pathological characteristics of the patients. Kaplan-Meier survival curve was used to analyze the relationship between DACH1 methylation status and prognostic survival of patients. RESULTS: The methylation rate of the DACH1 gene in esophageal cancer tumor tissue was 30.77% (32/104), which was higher than those in adjacent tissues (1.92%) and normal esophageal mucosa (0%) (P< 0.05). The methylation status of the DACH1gene in tumor tissues of patients did not correlate with the patient's age, gender, and pathological type (P> 0.05) but tumor differentiation, TNM staging, and lymph node metastasis(P< 0.05). The degree of tumor differentiation, TNM stage, and lymph node metastasis of patients are independent risk factors for the methylation status of the DACH1 gene. By March 2020, 89 of the 104 patients had died. Among them, the median survival foresophageal cancer patients with DACH1 gene methylation was 22 months, which was lower than 34 months of those without DACH1 methylation (P< 0.05). CONCLUSION Methylation of the DACH1 gene may be involved in the occurrence and progress of esophageal cancer. The degree of tumor differentiation, TNM stage, and lymph node metastasis of patients are independent risk factors for the methylation status of the DACH1 gene. Patients with esophageal cancer but unmethylated DACH1 gene have a longer prognostic survival.
Esophageal Neoplasms/pathology* ; Eye Proteins/genetics* ; Humans ; Lymphatic Metastasis ; Methylation ; Neoplasm Staging ; Prognosis ; Transcription Factors

This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma. We show that ERK5 expression is abundant in human lung cancer samples, and elevated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive potential. Importantly, we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser
A549 Cells ; Animals ; Cell Movement ; Epithelial-Mesenchymal Transition/genetics* ; Focal Adhesion Kinase 1/metabolism* ; Humans ; Lung Neoplasms/pathology* ; MAP Kinase Signaling System ; Mice ; Mitogen-Activated Protein Kinase 7/metabolism* ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasm Proteins/metabolism*

Prostate cancer is a complex, heterogeneous disease that mainly affects the older male population with a high-mortality rate. The mechanisms underlying prostate cancer progression are still incompletely understood. Beta-adrenergic signaling has been shown to regulate multiple cellular processes as a mediator of chronic stress. Recently, beta-adrenergic signaling has been reported to affect the development of aggressive prostate cancer by regulating neuroendocrine differentiation, angiogenesis, and metastasis. Here, we briefly summarize and discuss recent advances in these areas and their implications in prostate cancer therapeutics. We aim to provide a better understanding of the contribution of beta-adrenergic signaling to the progression of aggressive prostate cancer.
Cell Differentiation/genetics* ; Disease Progression ; Humans ; Male ; Neoplasm Metastasis ; Neovascularization, Pathologic/pathology* ; Neuroendocrine Cells/pathology* ; Prostatic Neoplasms/pathology* ; Receptors, Adrenergic, beta ; Signal Transduction

BACKGROUND: We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC. METHODS: The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression. Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown. The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients. RESULTS: FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration. FSTL1 knockdown up-regulated nuclear factor-κB (NF-κB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor (IκBα) in ccRCC cell lines. FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle, and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues (P < 0.001). The multivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325 (95% confidence interval 0.118-0.894). HIF-2α expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = - 0.229, P = 0.044). Intratumoral expression of HIF-2α, rather than HIF-1α, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038). CONCLUSIONS FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2α signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.
Adult ; Aged ; Aged, 80 and over ; Basic Helix-Loop-Helix Transcription Factors ; genetics ; Carcinoma, Renal Cell ; genetics ; pathology ; Cell Line, Tumor ; Cell Movement ; genetics ; Disease-Free Survival ; Epithelial-Mesenchymal Transition ; genetics ; Female ; Follistatin-Related Proteins ; genetics ; Gene Expression Regulation, Neoplastic ; genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; Male ; Middle Aged ; NF-kappa B ; genetics ; Neoplasm Metastasis ; Signal Transduction ; genetics ; Tumor Suppressor Proteins ; genetics