Development of a long noncoding RNA BC032469-dependent gold nanoparticle molecular beacon for the detection of gastric cancer cells.

Aim: Long noncoding RNA (lncRNA) BC032469-dependent gold nanoparticle molecular beacons (AuNP-MB) were constructed for the detection of gastric cancer cells. Materials & methods: The AuNP-MBs were prepared according to well-established procedures based on the Au-S interaction between the gold lattice and thiol functionalized oligonucleotides. More importantly, the stability and targeting ability of AuNP-MB were verified by a series of in vitro and in vivo experiments. Results: The lncRNA-dependent probes were successfully utilized for AuNP-MB-based intracellular imaging, with fluorescence effectively emitted in GC cells, but not in normal cells. Notably, such fluorescent emission was positively correlated with lncRNA BC032469 expression. Conclusion: The authors developed an effective fluorescent imaging probe for the recognition of gastric cancer cells.

CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification.

BACKGROUND: Aberrant expression of circular RNAs contributes to the initiation and progression of cancers, but the underlying mechanism remains elusive. METHODS: RNA-seq and qRT-PCR were performed to screen differential expressed circRNAs between gastric cancer tissues and adjacent normal tissues. Candidate circRNA (circMRPS35) was screened out and validated by qRT-PCR. Cell proliferation and invasion ability were determined by CCK-8 and cell invasion assays. RNA-seq, GO-pathway, RNA pull-down and ChIRP were further applied to search for detailed mechanism. RESULTS: Here, a novel circRNA named circMRPS35, was screened out by RNA-seq in gastric cancer tissues, whose expression is related to clinicopathological characteristics and prognosis in gastric cancer patients. Biologically, circMRPS35 suppresses the proliferation and invasion of gastric cancer cells in vitro and in vivo. Mechanistically, circMRPS35 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of FOXO1 and FOXO3a genes, which elicits acetylation of H4K5 in their promoters. Particularly, circMRPS35 specifically binds to FOXO1/3a promoter regions directly. Thus, it dramatically activates the transcription of FOXO1/3a and triggers subsequent response of their downstream target genes expression, including p21, p27, Twist1 and E-cadherin, resulting in the inhibition of cell proliferation and invasion. Moreover, circMRPS35 expression positively correlates with that of FOXO1/3a in gastric cancer tissues. CONCLUSIONS: Our findings not only reveal the pivotal roles of circMRPS35 in governing histone modification in anticancer treatment, but also advocate for triggering circMRPS35/KAT7/FOXO1/3a pathway to combat gastric cancer.

Gut microbiota: A new piece in understanding hepatocarcinogenesis.

The gut microbiota forms a symbiotic relationship with the host and benefits the body in many critical aspects of life. However, immune system defects, alterations in the gut microbiota and environmental changes can destroy this symbiotic relationship and may lead to diseases, including cancer. Due to the anatomic and functional connection of the gut and liver, increasing studies show the important role of the gut microbiota in the carcinogenesis of hepatocellular carcinoma (HCC). In this manuscript, we review the available evidence and analyze some potential mechanisms of the gut microbiota, including bacterial dysbiosis, lipopolysaccharide (LPS), and genotoxins, in the progression and promotion of HCC. Furthermore, we discuss the possible therapeutic applications of probiotics, chemotherapy modulation, immunotherapy, targeted drugs and fecal microbiota transplantation (FMT) in targeting the gut microbiota.

Submucosal Saline Injection Followed by Endoscopic Ultrasound versus Endoscopic Ultrasound Only for Distinguishing between T1a and T1b Esophageal Cancer.

PURPOSE: To examine whether submucosal saline injection (SSI) can improve traditional endoscopic ultrasound (EUS) accuracy in distinguishing between T1a and T1b stage esophageal squamous cell carcinoma (ESCC). EXPERIMENTAL DESIGN: Patients with T1N0M0 stage ESCC (n = 180) ages 18 to 85 years were enrolled between February 14, 2012 to June 4, 2018 at Sun Yat-sen University Cancer Center (Guangdong, China). They were randomly assigned (1:1) to receive either EUS examination after 3-5 mL SSI or EUS only examination. All the patients were referred to thoracic surgeons to receive endoscopic resection (ER) or esophagectomy 5 to 10 days after EUS examination. Standard EUS criteria were used to preoperatively stage the ESCC cases, and surgical pathology reports after referral were used to postoperatively stage the cases. The primary endpoint was the diagnostic accuracy of T1b staging [defined as the sum of the true positive (T1b) and true negative (T1a) cases divided by the total number of cases]. RESULTS: Among the per-protocol population, the SSI+EUS group (n = 81) was superior to the EUS-only group (n = 85) in terms of the diagnostic accuracy for T1b staging [93.8% (95% confidence interval (CI), 88.6-99.1) vs. 65.9% (95% CI, 55.8-76.0); P < 0.001]. The positive predictive value of SSI+EUS for diagnosing T1b ESCC reached 90.9% (95% CI, 81.1-100), which was significantly superior to that of EUS only [0.576 (0.450-0.702), P = 0.001]. CONCLUSIONS: SSI significantly improves the diagnostic accuracy of EUS in distinguishing between T1a and T1b ESCC, which might help avoid unnecessary esophagectomy and diagnostic ER.

Monensin may inhibit melanoma by regulating the selection between differentiation and stemness of melanoma stem cells.

Melanoma is the most lethal cutaneous malignancy that threatens human lives. Poor sensitivity to chemotherapy drugs and the high rate of resistance are the bottlenecks of melanoma treatment. Thus, new chemotherapy drugs are needed. Drug repurposing is a safe, economical and timesaving way to explore new chemotherapy for diseases. Here, we investigated the possibility of repurposing the antibiotic monensin as an anti-melanoma agent. Using three human melanoma cells and two nomal human cell lines as cell models, we found that monensin is obviously toxic to human melanoma cells while safe to nomal human cells. It effectively inhibited cell proliferation and viability, while promoted apoptosis and differentiation of human melanoma cells in vitro. By establishment of an animal model of transplanted human melanoma in nude mice, we demonstrated that monensin suppressed the growth of xenografts in vivo. At the same time, we found that melanogenesis increased and the ability of sphere and cloning forming of melanoma decreased under the treatment of monensin. Further detection about differentiation and pluripotent regulations were executed. Our results suggest that monensin is a potent inhibitor of melanoma, and its anti-tumor mechanism may be through promoting the final differentiation of melanoma stem cells and inhibiting their stemness maintenance.

Diverse regulatory manners of human telomerase reverse transcriptase.

Human telomerase reverse transcriptase (hTERT) is the core subunit of human telomerase and plays important roles in human cancers. Aberrant expression of hTERT is closely associated with tumorigenesis, cancer cell stemness maintaining, cell proliferation, apoptosis inhibition, senescence evasion and metastasis. The molecular basis of hTERT regulation is highly complicated and consists of various layers. A deep and full-scale comprehension of the regulatory mechanisms of hTERT is pivotal in understanding the pathogenesis and searching for therapeutic approaches. In this review, we summarize the recent advances regarding the diverse regulatory mechanisms of hTERT, including the transcriptional (promoter mutation, promoter region methylation and histone acetylation), post-transcriptional (mRNA alternative splicing and non-coding RNAs) and post-translational levels (phosphorylation and ubiquitination), which may provide novel perspectives for further translational diagnosis or therapeutic strategies targeting hTERT.

Regulation of the master regulator FOXM1 in cancer.

FOXM1 (forkhead box protein M1) is a critical proliferation-associated transcription factor that is widely spatiotemporally expressed during the cell cycle. It is closely involved with the processes of cell proliferation, self-renewal, and tumorigenesis. In most human cancers, FOXM1 is overexpressed, and this indicates a poor prognosis for cancer patients. FOXM1 maintains cancer hallmarks by regulating the expression of target genes at the transcriptional level. Due to its potential role as molecular target in cancer therapy, FOXM1 was named the Molecule of the Year in 2010. However, the mechanism of FOXM1 dysregulation remains indistinct. A comprehensive understanding of FOXM1 regulation will provide novel insight for cancer and other diseases in which FOXM1 plays a major role. Here, we summarize the transcriptional regulation, post-transcriptional regulation and post-translational modifications of FOXM1, which will provide extremely important implications for novel strategies targeting FOXM1.

Long noncoding RNA LINC00675 enhances phosphorylation of vimentin on Ser83 to suppress gastric cancer progression.

Long noncoding RNAs (lncRNAs) play a crucial role in cancer development, but few lncRNAs have been functionally characterized in gastric cancer (GC). Here, we reported an lncRNA LINC00675 whose expression was significantly decreased in GC tissues compared with the adjacent non-tumor tissues, and its low expression was associated with the poor survival of GC patients. Gain-and loss-of-function studies indicated that LINC00675 was a tumor suppressor because it repressed the proliferation, migration and invasion of GC cells in vitro and also inhibited the distal pulmonary and hepatic metastases of GC cells in vivo. Mechanistic investigations revealed that LINC00675 interacted with vimentin, a protein involved in cell metastasis, and enhanced its phosphorylation level on Ser83 to result in the collapse of vimentin filament in GC cells, thereby reducing cell metastasis. Taken together, our findings indicate that LINC00675 expression signature may serve as a novel biomarker for the diagnosis and prognosis of GC, and also highlight that LINC00675/vimentin complex may be a potentially therapeutic target of GC.

hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway.

BACKGROUND: hTERT has been reported involved in the proliferation and metastasis of gastric cancer, but the role of hTERT in gastric intestinal metaplasia, a premalignant lesion of the gastric mucosa was unknown. The aim of the present study was to investigate the role of hTERT in GIM and the effect of hTERT on CDX2 expression in gastric cells. RESULTS: Experiments showed that expression of hTERT was significantly higher in GIM than in normal gastric mucosa. Moreover, hTERT increased the KLF4 level via NF-κB during GIM. Furthermore, KLF4 is involved in the up-regulation of CDX2 induced by hTERT, and hTERT can interact with p50, thereby increasing the level of CDX2. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expression of hTERT in gastric intestinal metaplasia tissue. Then, effect of hTERT on the expression of CDX2 was detected by qRT-PCR, WB and dual luciferase experiment. The role of p65 and p50 in the regulation of CDX2 were further detected by WB, CO-IP and ChIP. CONCLUSIONS: We may conclude that hTERT promotes GIM by up-regulating CDX2 via NF-κB signaling pathway.

Long Noncoding RNA in Digestive Tract Cancers: Function, Mechanism, and Potential Biomarker.

Digestive tract cancers (DTCs) are a leading cause of cancer-related death worldwide. Current therapeutic tools for advanced stage DTCs have limitations, and patients with early stage DTCs frequently have a missed diagnosis due to shortage of efficient biomarkers. Consequently, it is necessary to develop novel biomarkers for early diagnosis and novel therapeutic targets for treatment of DTCs. In recent years, long noncoding RNAs (lncRNAs), a class of noncoding RNAs with >200 nucleotides, have been shown to be aberrantly expressed in DTCs and to have an important role in DTC development: the expression profiles of lncRNAs strongly correlated with poor survival of patients with DTCs, and lncRNAs acted as oncogenes or tumor suppressor genes in DTC progression. In this review, we summarized the functional lncRNAs and expounded on their regulatory mechanisms in DTCs.