Knockdown of EIF2AK2-OAS1 axis reduces ATP production inducing AMPK phosphorylation to inhibit the malignant behavior of gastric cancer cells.

Energy metabolism has always been a hot topic in cancer progression and targeted therapy, and exploring the role of genes in energy metabolic pathways in cancer cells has become key to address this issue. Eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) plays regulatory roles in cancer and disorders of energy metabolism. Indeed, the role of EIF2AK2 in energy metabolism has been underestimated. The aim of this study is to reveal the expression specificity of EIF2AK2 in gastric cancer (GC) progression and metastasis, and to demonstrate the role of EIF2AK2 in energy metabolism, cytoskeleton, proliferation, death and metastasis pathways in GC cells. Mechanistically, EIF2AK2 overexpression promoted cytoskeleton remodeling and ATP production, mediated cell proliferation and metastasis, upregulated OAS1 expression, decreases p-AMPK expression and inhibited apoptosis in GC cells. Conversely, knockdown of EIF2AK2 resulted in the opposite effect. However, overexpression of OAS1 mediated the upregulation of mitochondrial membrane potential and promoted ATP production and NAD+/NADH ratio, but knockdown of OAS1 inhibited the above effects. In addition, knockdown of OAS1 had no effect on EIF2AK2 expression, but inhibited AMPK and upregulated p-AMPK expression. In conclusion, our study identified EIF2AK2 and OAS1 as previously undescribed regulators of energy metabolism in GC cells. We hypothesized that EIF2AK2-OAS1 axis may regulate energy metabolism and inhibit cellular malignant behavior in cancer cells by affecting ATP production to induce AMPK phosphorylation, suggesting EIF2AK2 as a potential therapeutic target for cancer cell progression.

YTHDF1 enhances stemness and chemoresistance in triple-negative breast cancer cells by upregulating SIAH2.

Triple-negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer, and chemoresistance is the major determinant of TNBC treatment failure. This study explores the molecular mechanism of TNBC chemoresistance. The Cancer Genome Atlas, breast cancer integrative platform, and GEPIA databases were used to analyze the expression and correlation of YTHDF1 and seven in absentia homology 2 (SIAH2) in breast cancer. Knockdown of YTHDF1 and SIAH2, or overexpression of SIAH2 in vitro and in vivo, was conducted to evaluate the impact of changes in YTHDF1 and SIAH2 expression on TNBC cell proliferation, apoptosis, stemness, drug resistance, and Hippo pathway gene expression. YTHDF1 and SIAH2 were highly expressed in breast cancer patients and TNBC cells. Knockdown of YTHDF1 and SIAH2 significantly inhibited proliferation and stemness and promoted apoptosis and chemosensitivity of TNBC cells. Mechanistically, the knockdown of YTHDF1 inhibited the expression of SIAH2, thereby downregulating the Hippo pathway, which inhibited proliferation and stemness and promoted apoptosis and chemosensitivity of TNBC cells. The current findings revealed the regulatory mechanism of YTHDF1 in TNBC and clarified the role of the YTHDF1/SIAH2 axis in TNBC drug resistance and stemness. This could provide new insights into the vital role of targeting YTHDF1/SIAH2 to suppress drug resistance and stemness in TNBC cells.

Targeting the mitochondrial calcium uniporter inhibits cancer progression and alleviates cisplatin resistance in esophageal squamous cell carcinoma.

Cisplatin is the standard chemotherapeutic drug used for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired cisplatin resistance is the primary obstacle to prolonging patient survival time. Here, the therapeutic effects of mitochondrial calcium uniporter (MCU) inhibition on tumor growth and cisplatin resistance in ESCC were assessed. MCU was stably overexpressed or knocked down in three ESCC cell lines and three cisplatin­resistant ESCC cell lines. Then, proliferation, migration, and mitochondrial membrane potential (MMP) were measured by colony formation, wound healing, Transwell, and JC­1 staining assays. MCU, MICU2, MICU1, and PD­L1 levels were detected through western blotting and immunofluorescence. ESCC and cisplatin­resistant ESCC xenograft mouse models were established. After MCU knockdown, tumor volume was measured. The expression levels of proliferation markers (CyclinD1 and Ki­67), MICU1/2, PD­L1, epithelial-mesenchymal transition (EMT) markers (vimentin, ß­catenin, and E­cadherin), and the angiogenesis marker CD34 were detected through western blotting, immunohistochemistry, or immunofluorescence. The results showed that MCU overexpression significantly promoted proliferation, migration, and MMP in ESCC cells and cisplatin­resistant ESCC cells. However, proliferation, migration, and MMP were suppressed following MCU knockdown. In ESCC cells, MCU overexpression markedly increased MICU2, MICU1, and PD­L1 levels, and the opposite results were observed when MCU was stably knocked down. Similarly, MCU inhibition decreased MICU2, MICU1, and PD­L1 expression in cisplatin­resistant ESCC cells. Moreover, MCU knockdown substantially decreased tumor growth, EMT, and angiogenesis in ESCC and cisplatin­resistant ESCC xenograft mice. Collectively, targeting MCU may inhibit cancer progression and alleviate cisplatin resistance in ESCC.

Incidence trends and disparities in Helicobacter pylori related malignancy among US adults, 2000-2019.

Background: Helicobacter pylori (H. pylori) is closely related to the carcinogenesis of gastric cancer (GC) and gastric non-Hodgkin lymphoma (NHL). However, the systemic trend analysis in H. pylori-related malignancy is limited. We aimed to determine the national incidence trend in non-cardia GC, cardia GC, and gastric NHL in the US during 2000-2019. Method: In this population-based study, we included 186,769 patients with a newly diagnosed H. pylori-related malignancy, including non-cardia GC, cardia GC, and gastric NHL from the Surveillance, Epidemiology, and End Results (SEER) Registry from January 1, 2000 to December 31, 2019. We determined the age-adjusted incidence of three H. pylori-related malignancies respectively. Average annual percentage change (AAPC) in 2000-2019 was calculated to describe the incidence trends. Analyses were stratified by sex, age, race and ethnicity, geographic location and SEER registries. We also determined the 5-year incidence (during 2015-2019) by SEER registries to examine the geographic variance. Results: The incidence in non-cardia GC and gastric NHL significantly decreased during 2000-2019, while the rate plateaued for cardia GC (AAPCs, -1.0% [95% CI, -1.1%-0.9%], -2.6% [95% CI, -2.9%-2.3%], and -0.2% [95% CI, -0.7%-0.3%], respectively). For non-cardia GC, the incidence significantly increased among individuals aged 20-64 years (AAPC, 0.8% [95% CI, 0.6-1.0%]). A relative slower decline in incidence was also observed for women (AAPC, -0.4% [95% CI, -0.6%-0.2%], P for interaction < 0.05). The incidence of cardia GC reduced dramatically among Hispanics (AAPC, -0.8% [95% CI, -1.4%-0.3%]), however it increased significantly among nonmetropolitan residents (AAPC, 0.8% [95% CI, 0.4-1.3%]). For gastric NHL, the decreasing incidence were significantly slower for those aged 20-64 years (AAPC, -1.5% [95% CI, -1.9-1.1%]) and Black individuals (AAPC, -1.3% [95% CI, -1.9-1.1%]). Additionally, the highest incidence was observed among Asian and the Black for non-cardia GC, while Whites had the highest incidence of cardia GC and Hispanics had the highest incidence of gastric NHL (incidence rate, 8.0, 8.0, 3.1, and 1.2, respectively) in 2019. Geographic variance in incidence rates and trends were observed for all three H. pylori-related malignancies. The geographic disparities were more pronounced for non-cardia GC, with the most rapid decline occurring in Hawaii (AAPC, -4.5% [95% CI, -5.5-3.6%]) and a constant trend in New York (AAPC 0.0% [95% CI, -0.4-0.4%]), the highest incidence in Alaska Natives, and the lowest incidence among Iowans (14.3 and 2.3, respectively). Conclusion: The incidence of H. pylori-related cancer declined dramatically in the US between 2000 and 2019, with the exception of cardia GC. For young people, a rising trend in non-cardia GC was noted. Existence of racial/ethnic difference and geographic diversity persists. More cost-effective strategies of detection and management for H. pylori are still in demand.

A network meta-analysis of curative effect of different treatment methods on patients with brain metastasis of breast cancer.

BACKGROUND: Breast cancer (BC) is a malignant tumor with the highest incidence rate worldwide, and its incidence of breast cancer brain metastases is increased in recent years. Although significant progress has been made in the systematic treatment of BC that of breast cancer brain metastases is still very difficult. Organically integrating local and systemic therapies remains an urgent problem to be solved. In this study, a network meta-analysis was performed to collect the treatment effects of different treatment measures on patients with BC brain metastasis in recent years, evaluate and screen the current best clinical treatment scheme, and assist doctors in formulating clinical treatment schemes. METHODS: Keywords were used to search databases, such as the Chinese Journal Full-text Database, VIP Chinese Science and Technology Journal Full-text Database (VP-CSJFD), Wanfang Data Journal Paper Resources (Wangfang), PubMed, the Cochrane Library, and EMBASE. The retrieval period was from the establishment of each database to February 2022. Qualified randomized controlled studies were screened according to the inclusion and exclusion criteria, and Stata 16 software was adopted for mesh meta-analysis of binary variable data. Using R4 0.2 software, and calling GeMTC and JAGS packages in R software, the Bayesian network model analysis of survival data was completed. CONCLUSION: Combined with overall response rate, disease control rate, and overall survival, whole-brain radiation therapy + 3-dimensional conformal radiation therapy + Che may be the intervention measure with the highest objective remission rate for patients with brain metastasis of BC, besides, it may also be the intervention measure of the highest disease control rate in patients after treatment. In contrast, WBRT + Che may be the intervention with the lowest overall survival risk ratio after treatment.

Pivotal models and biomarkers related to the prognosis of breast cancer based on the immune cell interaction network.

The effect of breast cancer heterogeneity on prognosis of patients is still unclear, especially the role of immune cells in prognosis of breast cancer. In this study, single cell transcriptome sequencing data of breast cancer were used to analyze the relationship between breast cancer heterogeneity and prognosis. In this study, 14 cell clusters were identified in two single-cell datasets (GSE75688 and G118389). Proportion analysis of immune cells showed that NK cells were significantly aggregated in triple negative breast cancer, and the proportion of macrophages was significantly increased in primary breast cancer, while B cells, T cells, and neutrophils may be involved in the metastasis of breast cancer. The results of ligand receptor interaction network revealed that macrophages and DC cells were the most frequently interacting cells with other cells in breast cancer. The results of WGCNA analysis suggested that the MEblue module is most relevant to the overall survival time of triple negative breast cancer. Twenty-four prognostic genes in the blue module were identified by univariate Cox regression analysis and KM survival analysis. Multivariate regression analysis combined with risk analysis was used to analyze 24 prognostic genes to construct a prognostic model. The verification result of our prognostic model showed that there were significant differences in the expression of PCDH12, SLIT3, ACVRL1, and DLL4 genes between the high-risk group and the low-risk group, which can be used as prognostic biomarkers.

Mitochondrial calcium uniporter promotes cell proliferation and migration in esophageal cancer.

Increasing evidence has suggested that mitochondrial calcium uniporter (MCU) is involved in various types of cancer. However, its functions remain unclear in esophageal cancer. The aim of the present study was to explore its abnormal expression and clinical implications in esophageal cancer. A total of 110 patients with esophageal cancer were enrolled in the study. Western blotting was performed to examine the protein expression levels of MCU in 8 pairs of esophageal cancer and adjacent normal tissues. Using immunochemistry, a total of 110 esophageal cancer specimens were analyzed to identify the association between MCU expression and clinicopathological features of patients with esophageal cancer. Furthermore, immunofluorescence of MCU was performed. Pearson's correlation analysis was performed between MCU and hypoxia inducible factor (HIF)-1α/VEGF/E-cadherin/Vimentin expression based on western blotting. After KYSE-150 and TE-1 cells were treated with the MCU agonist Spermine and a small interfering RNA against MCU (si-MCU), a series of functional assays were performed, including Cell Counting Kit-8, colony formation and Transwell assays. The results revealed that, compared with in adjacent normal tissues, MCU was highly expressed in esophageal cancer tissues. MCU expression was significantly associated with depth of invasion, lymph node metastasis, TNM stage and distant metastasis. Moreover, MCU was significantly correlated with HIF-1α/VEGF/E-cadherin/Vimentin in esophageal cancer tissues. MCU overexpression promoted VEGF, MMP2, Vimentin and N-cadherin expression, while it inhibited E-cadherin expression in KYSE-150 and TE-1 cells, and opposite results were observed after transfection with si-MCU. Furthermore, MCU overexpression accelerated the proliferation and migration of KYSE-150 and TE-1 cells. Thus, the current findings suggested that high MCU expression may participate in cell proliferation, migration and epithelial-mesenchymal transition in esophageal cancer.

Nonhormonal Hot Flash Management for Breast Cancer Survivors: A Systematic Review and Network Meta-Analysis.

MATERIALS AND METHODS: We conducted a systematic literature search in PubMed, Cochrane Central Register of Controlled Trials, Embase, Chinese Biomedicine Database (CBM), China National Knowledge Infrastructure (CNKI), Wan Fang, and VIP up to May 2018. Randomized controlled trials (RCTs) reporting nonhormonal hot flash treatments for breast cancer survivors were included. Primary outcome measurements were hot flash frequency and hot flash score of posttreatment. The methodological quality of each study was assessed with Cochrane's risk of bias tool. RESULTS: 16 RCTs involving 2,349 participants were included. The nonhormonal therapies used in the included studies were classified as follows: lifestyle changes, mind-body techniques, dietary/supplements, SSRIs/SNRIs, other medications, and other therapies. Pairwise meta-analysis showed that the general effect of nonhormonal management was statistically more effective than no treatment/placebo/sham in reducing hot flash frequency (SMD = -0.60, 95% CI [-1.13, -0.06]; P=0.03)) and hot flash score (SMD = -0.38, 95% CI [-0.68, -0.08]). For hot flash frequency, results from the NMA showed that there was no statistically significant difference between any two of the nonhormonal treatments. Another NMA result indicated that acupuncture (other therapies) was 16.05 points more effective in reducing hot flash scores than no treatment/waitlist (SMD = -16.05, 95% CI [-30.2, -1.99]). These results were statistically significant. Acupuncture was also ranked the optimal nonhormonal therapy for both hot flash frequency and hot flash score. The safety analysis showed that there were few related adverse events during acupuncture and that drug related adverse reactions could have also occurred in studies using drug interventions. CONCLUSIONS: This network meta-analysis comparing nonhormonal treatments suggested that acupuncture might be more effective in improving hot flashes for breast cancer survivors. A pronounced placebo response was found during hot flash treatments. The evidence of safety for nonhormonal therapies was also insufficient. Therefore, at present, we cannot make confirmative recommendations of nonhormonal hot flash management for breast cancer survivors. This study is registered with PROSPERO (CRD42018082008).

Association Between Nitrite and Nitrate Intake and Risk of Gastric Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND Studies have shown inconsistent associations of nitrite and nitrate intake with the risk of gastric cancer or its associated mortality. We performed a meta-analysis of observational studies to evaluate the correlation of nitrite and nitrate intake with the risk of gastric cancer. MATERIAL AND METHODS We searched for studies reporting effect estimates and 95% confidence intervals (CIs) of gastric cancer in PubMed, EMBASE, and the Cochrane Library through November 2018. The summary results of the included studies were pooled using a random-effects model. RESULTS Eighteen case-control and 6 prospective cohort studies recruiting 800 321 participants were included in this study. The summary results indicated that the highest (odds ratio [OR], 1.27; 95%CI, 1.03-1.55; P=0.022) or moderate (OR: 1.12; 95%CI, 1.01-1.26; P=0.037) nitrite intake were associated with a higher risk of gastric cancer. However, we noted that high (OR, 0.81; 95%CI, 0.68-0.97; P=0.021) or moderate (OR, 0.86; 95%CI, 0.75-0.99; P=0.036) nitrate intakes were associated with a reduced risk of gastric cancer. These associations differed when stratified by publication year, study design, country, the percentage of male participants, assessment of exposure, adjusted model, and study quality. CONCLUSIONS High or moderate nitrite intake was associated with higher risk of gastric cancer, whereas high or moderate nitrate intake was correlated with lower risk of gastric cancer.

miR-199b-5p inhibits triple negative breast cancer cell proliferation, migration and invasion by targeting DDR1.

Triple negative breast cancer (TNBC) has received increasing attention from oncologists worldwide due to its poor prognosis and paucity of targeted therapies. MicroRNAs (miRs) are a group of small non-coding RNAs that are responsible for the post-transcriptional regulation of various target genes. The present study demonstrated that the expression of miR-199b-5p in breast cancer tissue was significantly reduced compared with that in normal breast tissues by reverse transcription-quantitative polymerase chain reaction. In addition, western blot analysis and luciferase reporter assays revealed that miR-199b-5p in TNBC cells inhibited discoidin domain receptor tyrosine kinase 1 expression by directly targeting its 3'-untranslated region. Furthermore, miR-199b-5p markedly suppressed the proliferation and invasion of TNBC cells, as demonstrated by using wound-healing, migration, invasion and proliferation assays. Collectively, these results indicate that miR-199b-5p may be a novel alternative therapeutic target for TNBC.