Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with notable metabolic reprogramming, yet the pivotal metabolic feature driving ESCC progression remains elusive. Here, we show that methionine cycle exhibits robust activation in ESCC and is reversely associated with patient survival. ESCC cells readily harness exogenous methionine to generate S-adenosyl-methionine (SAM), thus promoting cell proliferation. Mechanistically, methionine augments METTL3-mediated RNA m6A methylation through SAM and revises gene expression. Integrative omics analysis highlights the potent influence of methionine/SAM on NR4A2 expression in a tumor-specific manner, mediated by the IGF2BP2-dependent stabilization of methylated NR4A2 mRNA. We demonstrate that NR4A2 facilitates ESCC growth and negatively impacts patient survival. We further identify celecoxib as an effective inhibitor of NR4A2, offering promise as a new anti-ESCC agent. In summary, our findings underscore the active methionine cycle as a critical metabolic characteristic in ESCC, and pinpoint NR4A2 as a novel methionine-responsive oncogene, thereby presenting a compelling target potentially superior to methionine restriction.

Fibronectin promotes tumor progression through integrin αvß3/PI3K/AKT/SOX2 signaling in non-small cell lung cancer.

The tumor microenvironment, especially the extracellular matrix (ECM), is strongly associated with tumor cell proliferation and metastasis. Numerous studies have provided evidence suggesting that fibronectin (FN) in ECM supports cancer cell escape and contributes to cell migration, resulting in distant cancer metastasis and poor outcomes in patients. In our study, it was demonstrated that FN expression was elevated in tumor tissues from highly malignant NSCLC patients, compared to those with low malignancy (p = 0.0076). Importantly, FN promoted proliferative phenotypes and strengthened tumorigenesis capabilities in NSCLC cells, including A549 and Lewis cells, leading to sustained tumor growth in vivo. Mechanistically, it was identified that FN facilitated the activation of the integrin αvß3/PI3K/AKT signaling pathway, which subsequently upregulated tumor stemness through the downstream transcription factor SOX2. Blockade of integrin αvß3 signal efficiently suppressed NSCLC proliferation and tumorigenesis both in vitro and in vivo. In conclusion, our study demonstrated that extracellular FN could facilitate NSCLC development through the integrin αvß3/PI3K/AKT/SOX2 signaling pathway. Blockade of integrin αvß3 could efficiently enhance the anticancer effects of chemotherapy, offering an innovative approach for clinical NSCLC therapy.

Active post-transcriptional regulation and ACLY-mediated acetyl-CoA synthesis as a pivotal target of Shuang-Huang-Sheng-Bai formula for lung adenocarcinoma treatment.

BACKGROUND: New therapeutic approaches are required to improve the outcomes of lung cancer (LC), a leading cause of cancer-related deaths worldwide. Chinese herbal medicine formulae widely used in China provide a unique opportunity for improving LC treatment, and the Shuang-Huang-Sheng-Bai (SHSB) formula is a typical example. However, the underlying mechanisms of action remains unclear. PURPOSE: This study aimed to confirm the efficacy of SHSB against lung adenocarcinoma (LUAD), which is a major histological type of LC, unveil the downstream targets of this formula, and assess the clinical relevance and biological roles of the newly identified target. METHODS: An experimental metastasis mouse model and a subcutaneous xenograft mouse model were used to evaluate the anti-cancer activity of SHSB. Multi-omics profiling of subcutaneous tumors and metabolomic profiling of sera were performed to identify downstream targets, especially the metabolic targets of SHSB. A clinical trial was conducted to verify the newly identified metabolic targets in patients. Next, the metabolites and enzymes engaged in the metabolic pathway targeted by SHSB were measured in clinical samples. Finally, routine molecular experiments were performed to decipher the biological functions of the metabolic pathways targeted by SHSB. RESULTS: Oral SHSB administration showed overt anti-LUAD efficacy as revealed by the extended overall survival of the metastasis model and impaired growth of implanted tumors in the subcutaneous xenograft model. Mechanistically, SHSB administration altered protein expression in the post-transcriptional layer and modified the metabolome of LUAD xenografts. Integrative analysis demonstrated that SHSB markedly inhibited acetyl-CoA synthesis in tumors by post-transcriptionally downregulating ATP-citrate lyase (ACLY). Consistently, our clinical trial showed that oral SHSB administration declined serum acetyl-CoA levels of patients with LC. Moreover, acetyl-CoA synthesis and ACLY expression were both augmented in clinical LUAD tissues of patients, and high intratumoral ACLY expression predicted a detrimental prognosis. Finally, we showed that ACLY-mediated acetyl-CoA synthesis is essential for LUAD cell growth by promoting G1/S transition and DNA replication. CONCLUSION: Limited downstream targets of SHSB for LC treatment have been reported in previous hypothesis-driven studies. In this study, we conducted a comprehensive multi-omics investigation and demonstrated that SHSB exerted its anti-LUAD efficacy by actively and post-transcriptionally modulating protein expression and particularly restraining ACLY-mediated acetyl-CoA synthesis.

[Effects of a Traditinal Chinese Medicine Compound Regimen on Differentiation and Proliferation of Acute Myeloid Leukemia Cell Lines].

OBJECTIVE: To study the effect of traditional chinese medicine (TCM) compound on myeloid leukemia cells and to explore its anti-leukemic mechanism. METHODS: Myeloid leukemia cell lines were cultured in vitro and treated with TCM compound. The proliferation of the leukemia cells was measured by CCK8 method. The differentiation of the leukemia cells was evaluated by using Wright＇s staining method and by light microscopy, and the expression of differentiation-related surface antigens such as CD11B was measured and by flow cytometry, the apoptosis of the leukemia cells was detected by flow cytometry with using Annexin V staining. RESULTS: Compared with untreated 4 leukemia cell lines HL-60, MOLM-13, MV4-11, AML-M5, the proliferations of 4 leukemia cells treated with different concentrations of TCM compound decreased (P<0.05), and their proliferation inhibition were in a dose-dependent manner (r=0.9236; r=0.7488; r=0.8889; r=0.8119); compared with HL-60 and AML-M5 leukemia cells, the drug-treated 2 leukemia cells displayed obvious differentiated changes; compared with untreated HL-60 leukemia cell line, the expression of surface antigen CD11B increased by 85%±7.13% in HL-60 cells treated IC50 concentration of drug; compared with untreated AML-M5 leukemia cell line, the apoptotic rate of AML-M5 treated with 1.5 and 2 µl doses of TCM compound increased. (P<0.05). CONCLUSION: The traditional chinese medicine compound may inhibit the proliferation of leukemia cell lines mainly by inducing leukemia cell differentiation and apoptosis.

Prognostic significance of overexpressed matrix metalloproteinase-2, mouse-double minute: 2 homolog and epidermal growth factor receptor in non-small cell lung cancer.

PURPOSE: To evaluate the rate of overexpression of matrix metalloproteinase-2 (MMP2), mouse double minute 2 homolog (MDM2) and epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC), and evaluate their correlation with clinicopathological parameters and prognosis. METHODS: This was a prospective cohort study conducted from 2003 to 2008 among 184 NSCLC patients who underwent tumor resection. Each patient's clinical history and tumor characteristics were obtained from histopathology reports and medical records. EGFR, MDM2 and MMP2 expression were assessed by immunohistochemical (IHC) staining of the tissue specimens. RESULTS: MDM2 overexpression was observed in 70 (38%) of the patients studied, and was significantly higher in younger patients (p=0.01). Only 46 (25%) of patients had overexpression of MMP2. EGFR positive staining occurred in 105 (57%percnt;) of the evaluated tumor specimens and was more frequent in specimens with squamous cell carcinoma (p<0.001), the elderly (p<0.001), and in smokers (p<0.001). Independent risk factors for mortality were older age (adjusted odds ratio/aOR 1.3=), being a smoker (aOR 10), having stage II disease (aOR 10.8) or stage III/IV disease (aOR 28.3), expression of EGFR (aOR 5.9) and MMP2 (aOR 4.1). However, the expression of MDM2 independently predicted a reduced risk of death (aOR 0.3). CONCLUSION: Overexpression of MMP2 and EGFR were independent risk factors for mortality in NSCLC patients, while overexpression of MDM2 independently predicted a reduced risk of death.

miR-106a promotes growth and metastasis of non-small cell lung cancer by targeting PTEN.

MicroRNAs are a class of small non-coding RNAs that play essential roles in cancer development and progression. Recent studies suggested that abnormal expression of miRNAs occurs frequently in non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues. In this study, we investigated the expression and the biological roles of miR-106a in non-small cell lung cancer. Our results showed that miR-106a was up-regulated in NSCLC tissues and cell lines. Inhibition of miR-106a in NSCLC cells substantially inhibited cell proliferation, migration, and invasion. Phosphatase and tensin homolog (PTEN) was identified as a direct target of miR-106a, and over-expression of miR-106a suppressed PTEN by direct binding to its 3'-untranslated region (3'-UTR). Furthermore, the presence of miR-106a was inversely correlated with PTEN in NSCLC tissues. Overall, this study suggested that miR-106a inhibited the growth and metastasis of NSCLC cells by decreasing PTEN expression. These data provide novel insights with potential therapeutic applications for the treatment of NSCLC.

Transurethral endoscopic treatment of seminal vesicle cysts (report of seven cases).

OBJECTIVE: Seminal vesicle cysts are a rare disorder of the male reproductive system. The goal of this report was to summarize the radiological manifestations and transurethral endoscopic treatment of large seminal vesicle cysts. MATERIALS AND METHODS: The clinical data of seven cases of giant seminal vesicle cysts, including their symptoms, radiological images, transurethral endoscopic treatment, and postoperative follow-up, were retrospectively reviewed. RESULTS: Computerized tomography and magnetic resonance imaging (MRI) demonstrated the cysts behind the bladder, above the prostate, and away from the midline. The lesions ranged in size from 8.26 cm × 7.98 cm × 4.85 cm to 9.27 cm × 8.95 cm × 8.15 cm. Two cases were associated with ipsilateral renal and ureteral agenesis and were classified as congenital malformations. The other five cases were simple seminal vesicle cysts thought to be secondary to acquired ejaculatory duct obstruction. All seven cases were successfully treated using transurethral endoscopic unroofing with cautery of the mucosa. All the seminal vesicle cysts were confirmed by pathologic examination. No malignant disease was found. All preoperative symptoms resolved after surgery. No complications were observed. No patient developed abnormalities of erection, ejaculation, or orgasm. No bladder or rectal injuries were noted. The seminal vesicle cysts were significantly decreased in size or absent 3-6 months after treatment. CONCLUSION: MRI best characterized seminal vesical cysts and their cause. Transurethral unroofing with cautery of the mucosa is an extension of well-accepted cystoscopic techniques. It is safe, easy to perform, and effective. It is the preferred method for the treatment of large seminal vesicle cysts.

LncRNA HMlincRNA717 is down-regulated in non-small cell lung cancer and associated with poor prognosis.

INTRODUCTION: Long non coding RNAs (lncRNAs) have emerged recently as major players in tumor biology and may be used for cancer diagnosis, prognosis, and potential therapeutic targets. The lncRNA HMlincRNA717, a newly identified lncRNA, was demonstrated to be down-regulated in gastric cancer. However, little is known about its role in non small cell lung cancer (NSCLC). METHODS: Expression of lncRNA HMlincRNA717 in tumor and their matched non-tumor tissues was determined by quantitative real-time PCR (qRT-PCR) in NSCLC patients. Then, we analyzed the potential relationship between lncRNA HMlincRNA717 expression levels in tumor tissues and clinicopathological features of NSCLC, and clinical outcome. RESULTS: lncRNA HMlincRNA717 expression level was significantly decreased in NSCLC tissues in comparison to adjacent non-tumor tissues. It was also proved that HMlincRNA717 expression was to be associated with NSCLC histological grade, and lymph node metastasis. In addition, survival analysis proved that down-regulated HMlincRNA717 expression was associated with poor overall survival of NSCLC patients. Multivariate survival analysis also proved that HMlincRNA717 was an independent prognostic factor for NSCLC patients. CONCLUSIONS: The present study showed the down-regulation of HMlincRNA717 and its association with tumor progression in human NSCLC. It also provided that HMlincRNA717 expression was an independent prognostic factor for patients with NSCLC, which might be a potential prognostic biomarker and therapeutic target for NSCLC.