CircVIRMA enhances cell malignant behavior by governing the miR-452-5p/CREBRF pathway in cervical cancer.

Our current study aimed to investigate the role and mechanism of circVIRMA in cervical cancer (CC) progression. CircVIRMA, microRNA-452-5p (miR-452-5p) and CREB3 regulatory factor (CREBRF) mRNA levels were examined in CC via quantitative real-time PCR (qRT-PCR). The protein level of CREBRF in CC was checked by Western blot. Cell Counting Kit-8 (CCK-8), colony formation, 5-Ethynyl-2'-deoxyuridine (EdU) staining, cell cycle, flow cytometry and transwell assays were conducted to estimate the effects of circVIRMA on malignant phenotypes of CC tumors. Western blot was used to measure related marker protein levels. The interaction between miR-452-5p and circVIRMA or CREBRF was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. Xenograft assay was used to assess the effect of circVIRMA on tumor growth in vivo. Immunohistochemistry (IHC) assay was performed to detect Ki-67 expression in tissues of mice. CircVIRMA and CREBRF levels were upregulated, while miR-452-5p was downregulated in CC tissues and cells. CircVIRMA silencing restrained CC cell proliferation, migration and invasion whereas induced apoptosis in vitro. In addition circVIRMA knockdown markedly attenuated xenograft tumor growth in vivo. circVIRMA was an efficient molecular sponge for miR-452-5p, and negatively regulated miR-452-5p expression. circVIRMA regulated CREBRF expression to modulate CC progression via miR-452-5p. MiR-452-5p downregulation reversed the effects of circVIRMA knockdown on CC progression. MiR-452-5p directly targeted CREBRF, and CREBRF overexpression partly restored the impact of miR-452-5p mimics on CC progression. circVIRMA mediated CC progression via regulating miR-452-5p/CREBRF axis, providing a novel therapeutic target for CC treatment.

Correction: Identification of serum prognostic marker miRNAs and construction of microRNA-mRNA networks of esophageal cancer.

[This corrects the article DOI: 10.1371/journal.pone.0255479.].

Abnormal metabolism in hepatic stellate cells: Pandora's box of MAFLD related hepatocellular carcinoma.

Metabolic associated fatty liver disease (MAFLD) is a significant risk factor for the development of hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs), as key mediators in liver injury response, are believed to play a crucial role in the repair process of liver injury. However, in MAFLD patients, the normal metabolic and immunoregulatory mechanisms of HSCs become disrupted, leading to disturbances in the local microenvironment. Abnormally activated HSCs are heavily involved in the initiation and progression of HCC. The metabolic disorders and abnormal activation of HSCs not only initiate liver fibrosis but also contribute to carcinogenesis. In this review, we provide an overview of recent research progress on the relationship between the abnormal metabolism of HSCs and the local immune system in the liver, elucidating the mechanisms of immune imbalance caused by abnormally activated HSCs in MAFLD patients. Based on this understanding, we discuss the potential and challenges of metabolic-based and immunology-based mechanisms in the treatment of MAFLD-related HCC, with a specific focus on the role of HSCs in HCC progression and their potential as targets for anti-cancer therapy. This review aims to enhance researchers' understanding of the importance of HSCs in maintaining normal liver function and highlights the significance of HSCs in the progression of MAFLD-related HCC.

Circ_0001982 aggravates breast cancer development through the circ_0001982-miR-144-3p-GSE1 axis.

This study was designed to explore the role of circ_0001982 in breast cancer (BC) development. Quantitative real-time polymerase chain reaction and western blot analysis assays were used to determine circ_0001982, miR-144-3p, and gse1 coiled-coil protein (GSE1) expression. Functional assays were performed to evaluate cell proliferation, apoptosis, migration, and invasion. The glycolysis was analyzed with commercial kits. Dual-luciferase reporter assay and RNA immunoprecipitation assays were conducted to analyze the relationships among circ_0001982, miR-144-3p, and GSE1. A murine xenograft model assay was performed to determine circ_0001982-induced effects on BC cell tumor properties in vivo. Circ_0001982 expression was upregulated, but miR-144-3p was reduced in BC tissues and cells in comparison with normal breast tissues and normal human mammary epithelial cells. Circ_0001982 knockdown or miR-144-3p overexpression inhibited BC cell proliferation, glycolysis, migration and invasion, and promoted apoptosis. Circ_0001982 sponged miR-144-3p and negatively regulated miR-144-3p expression in BC cells. In addition, GSE1 was identified as a target mRNA of miR-144-3p. Ectopic GSE1 expression relieved circ_0001982 depletion-induced effects on BC cell tumor properties. Furthermore, circ_0001982 absence suppressed BC cell tumor properties in vivo. Circ_0001982 contributed to the BC cell tumor properties by regulating the miR-144-3p-GSE1 axis.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) versus conventional transarterial chemoembolization (cTACE) in colorectal liver metastasis: Efficacy, safety, and prognostic factors.

OBJECTIVE: To comparatively evaluate drug-eluting bead transarterial chemoembolization (DEB-TACE) and conventional transarterial chemoembolization (cTACE) for efficacy, safety, and related prognostic factors in the treatment of colorectal liver metastasis (CRLM). MATERIALS AND METHODS: This study retrospectively analyzed 75 patients with CRLM-administered DEB-TACE (n = 36) or cTACE (n = 39) between January 2016 and December 2017. Local control, survival outcome, and complications were compared between the two groups. Univariate and multivariate analyses of prognostic factors affecting progression-free survival (PFS) and overall survival (OS) were performed. RESULTS: The median follow-up in the two groups was 10.5 months (range, 0.5-22). Median PFS and OS in the DEB-TACE group were 10.0 and 13.0 months, respectively, and 6.0 and 8.5 months in the cTACE group, respectively (P = 0.009 and P = 0.008). The 3-, 6-, and 12-month OS rates in the DEB-TACE group were 100.0%, 94.4%, and 55.6%, respectively, and 92.3%, 71.8%, and 35.9% in the cTACE group, respectively. The 3-month OS rate (P = 0.083) showed no significant difference between the two groups, but significant differences were found in the 6- and 12-month OS rates (P = 0.008 and P = 0.030). Univariate and multivariate survival analyses showed that treatment method, tumor size, and tumor number were independent prognostic factors affecting PFS and OS. CONCLUSION: DEB-TACE has advantages over cTACE in prolonging PFS and OS in patients with CRLM. Treatment method, tumor number, and tumor size are important prognostic factors affecting PFS and OS. However, further multicenter and prospective trials are needed to confirm a deeper comparison between DEB-TACE and cTACE in patients with CRLM.

RAB10 promotes breast cancer proliferation migration and invasion predicting a poor prognosis for breast cancer.

RAB10, a member of the small GTPase family, has complex biological functions, but its role in breast cancer (BC) remains unclear. The aim of this study was to investigate the relationship between RAB10's role in BC, its biological functions, and BC prognosis. An online database was used to analyze the correlation between differential expression of RAB10 in BC and prognosis. The results of immunohistochemical assays in clinical cohorts were combined with the database analysis. The chi-square test and COX regression were employed to analyze the correlation between RAB10 and pathological features of BC. MTT, Transwell, and wound healing assays were conducted to detect BC cell proliferation, invasion, and metastatic ability. Bioinformatics techniques were employed to explore the correlation between RAB10 and BC tumor immune cell infiltration, and to speculate the biological function of RAB10 in BC and related signaling pathways. Our findings suggest that RAB10 expression is elevated in BC and is associated with HER2 status, indicating a poor prognosis for BC patients. RAB10 can promote the proliferation, migration, and invasion ability of BC cells in vitro. RAB10 is also associated with BC immune cell infiltration and interacts with multiple signaling pathways. RAB10 is a potential biomarker or molecular target for BC.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of olanzapine plus triple antiemetic regimen for the prevention of multiday highly emetogenic chemotherapy-induced nausea and vomiting (OFFER study).

Background: Evidence supports prophylactic use of olanzapine for the treatment of chemotherapy-induced nausea and vomiting (CINV). However, most studies to date have focused on patients with single-day highly emetogenic chemotherapy (HEC). Currently, administration of antiemetic therapies for nausea and vomiting induced by multiday chemotherapy regimens remains a challenge. In this study, we evaluated the efficacy of olanzapine combined with triple antiemetic therapy for the prevention of CINV in patients receiving multiday chemotherapy. Methods: We performed a randomized, double-blind, placebo-controlled phase 3 trial in 22 hospitals. Eligible patients were between 18 and 75 years old, were diagnosed with malignant solid tumors, and they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All the study participants were scheduled to be treated with chemotherapy regimens containing 3-day cisplatin (3-day total dose ≥75 mg/m2). Randomization was computer generated and stratified by gender and chemotherapy treatment history. Allocation was done via an interactive web response system. Enrolled patients were randomly assigned 1:1 to receive either 5 mg olanzapine or placebo orally before bedtime for 5 days combined with intravenous fosaprepitant (150 mg) 1 h before the administration of cisplatin on day 1, ondansetron hydrochloride intravenously, and dexamethasone orally 30 min before cisplatin from days 1 to 3. Dexamethasone was also administered at the same time on days 4 and 5. The primary endpoint was the proportion of subjects with complete response (no vomiting and no rescue therapy) within the overall phase (days 1-8) after starting chemotherapy. Baseline plasma concentrations of P-substance and 5-HT were measured for exploratory analysis. This study was registered at ClinicalTrials.gov, number NCT04536558. Findings: Between December 2020 and September 2021, 349 patients with malignant solid tumors were enrolled in the study, with 175 participants randomly assigned to receive olanzapine and 174 participants assigned to receive placebo. The proportion of patients who achieved a complete response in the overall phase was significantly higher in the olanzapine group than in the placebo group (69% vs. 58%, P = 0.031). A complete response benefit was observed in the olanzapine group versus the placebo group in almost all the subgroups. Four factors were considered significantly associated with complete response in multivariable analysis: treatment group, gender, baseline plasma concentration of 5-HT, and prior radiotherapy. All the reported adverse events associated with olanzapine administration were grades 1 and 2. Interpretation: Olanzapine (5 mg) combined with fosaprepitant, ondansetron, and dexamethasone was better than triple antiemetic therapy alone for patients receiving multiday chemotherapy regimens. Based on these results, the four-drug combination should be recommended as the best antiemetic regimen given to patients receiving multiday cisplatin-based chemotherapy and baseline plasma concentration of 5-HT may be used to identify individuals who are prone to CINV. However, all these findings need to be further validated in future studies. Funding: Jiangsu Hansoh Pharmaceutical Group Co., Ltd. provided research grant and study drugs for this investigator-initiated study.

MiR-30c facilitates natural killer cell cytotoxicity to lung cancer through targeting GALNT7.

BACKGROUND: MicroRNAs (miRNAs) have been reported to play important roles in regulating natural killer (NK) cell cytotoxicity to cancer cells. OBJECTIVE: This study aimed to investigate the effects and potential mechanism of miR-30c in regulating NK cell cytotoxicity to lung cancer cells. METHODS: Primary NK cells were derived from the peripheral blood of lung cancer and normal participants. Exosomes were isolated and validated via transmission electron microscopy and nanoparticle tracking analysis. The levels of miR-30c, polypeptide N-acetylgalactosaminyltransferase 7 (GALNT7) and proteins in PI3K/AKT pathway were determined using quantitative real-time polymerase chain reaction or western blot. Tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) levels and the cytotoxicity of effector NK cells to target lung cancer cells were measured via enzyme linked immunosorbent assay, cell apoptosis or xenograft experiments. The relationship between miR-30c and GALNT7 was analyzed by luciferase activity, RNA pull-down and RNA immunoprecipitation assays. And a xenograft mice model was established to verify the effect of miR-30c in regulating NK cell cytotoxicity to lung cancer cells in vivo. RESULTS: NK cell-derived exosomes carrying miR-30c, and miR-30c level was significantly downregulated in primary NK cells of lung cancer patients. MiR-30c overexpression promoted TNF-α and IFN-γ secretion and enhanced the cytotoxicity of interleukin 2 (IL-2)-treated NK cells to lung cancer cells, while knockdown of miR-30c played an opposite effect in regulating the cytotoxicity of NK cells to lung cancer cells. GALNT7 was a target of miR-30c and was negatively regulated by miR-30c. Besides, miR-30c targeted GALNT7 to exert its function in regulating NK cell cytotoxicity. Furthermore, GALNT7 prompted the activation of PI3K/AKT pathway in NK cells. Additionally, miR-30c overexpression enhanced NK cell cytotoxicity to lung cancer cells and inhibited tumor growth in vivo. CONCLUSION: miR-30c enhanced NK cell cytotoxicity to lung cancer cells via decreasing GALNT7 and inactivating the PI3K/AKT pathway, suggesting that regulating miR-30c expression maybe a promising approach for enhancing NK cell-based antitumor therapies.

A systematic review and meta-analysis comparing tumor progression and complications between radiofrequency ablation and thyroidectomy for papillary thyroid carcinoma.

Background: Papillary thyroid cancer (PTC) is the most frequent thyroid cancers worldwide. The efficacy and acceptability of radiofrequency ablation (RFA) in the treatment of PTC have been intensively studied. The aim of this study is to focus on extra detailed that may influent for PTC or papillary thyroid microcarcinoma (PTMC). Materials and methods: We identified a total of 1,987 records of a primary literature searched in PubMed, Embase, Cochrane Library, and Google Scholar by key words, from 2000 to 2022. The outcome of studies included complication, costs, and local tumor progression. After scrutiny screening and full-text assessment, six studies were included in the systematic review. Heterogeneity was estimated using I2, and the quality of evidence was assessed for each outcome using the GRADE guidelines. Results: Our review enrolled 1,708 patients reported in six articles in the final analysis. There were 397 men and 1,311 women in the analysis. Two of these studies involved PTC and four focused on PTMC. There were 859 patients in the RFA group and 849 patients in the thyroidectomy group. By contrast, the tumor progression of RFA group was as same as that surgical groups [odds ratio, 1.31; 95% CI, 0.52-3.29; heterogeneity (I2 statistic), 0%, p = 0.85]. The risk of complication rates was significantly lower in the RFA group than that in the surgical group [odds ratio, 0.18; 95% CI, 0.09-0.35; heterogeneity (I2 statistic), 40%, p = 0.14]. Conclusions: RFA is a safe procedure with a certain outcome for PTC. RFA can achieve a good efficacy and has a lower risk of major complications.

Transarterial chemoembolization combined with metformin improves the prognosis of hepatocellular carcinoma patients with type 2 diabetes.

Objective: The study aims to investigate the effect of metformin on Hepatocellular carcinoma (HCC) patients with type 2 diabetes mellitus (T2DM) who received transarterial chemoembolization (TACE) for the first time. Methods: From January 2016 to December 2019, T2DM patients diagnosed with HCC in Shandong Cancer Hospital and treated with TACE were included in this retrospective study. Overall survival (OS) and Progression-free survival (PFS) were compared between patients treated with metformin and other antidiabetics. Univariate and multivariate Cox regression models were used to evaluate the independent risk factors associated with OS and PFS. And sub-analysis was performed to investigate whether metformin could give a survival advantage in each Barcelona Clinic Liver Cancer (BCLC) stage of HCC. Propensity score matched (PSM) analyses based on patient and tumor characteristics were also conducted. Results: A total of 123 HCC patients with T2DM underwent TACE, of which 50 (40.65%) received treatment with metformin. For the whole cohort, the median OS (42 vs 32 months, p=0.054) and PFS (12 vs 7 months, P=0.0016) were longer in the metformin group than that in the non-metformin group. Multi-analysis revealed that BCLC stage, BMI (Body Mass Index), and metformin use were independent predictors of OS. Metformin use was independently associated with recurrence. After PSM, 39 matched pairs were identified. The use of metformin was associated with a numerically longer m OS (43 vs 35 months, P=0.183) than the use of other anti-diabetics. And the difference in median PFS (13 vs 7 months, p=0.018) between the metformin group and non-metformin group remained significant. Conclusion: The combination of transarterial chemoembolization and metformin may be associated with better OS and PFS in HCC patients with T2DM.

The hypoxia-inducible factor 1 inhibitor LW6 mediates the HIF-1α/PD-L1 axis and suppresses tumor growth of hepatocellular carcinoma in vitro and in vivo.

The low survival rate of hepatocellular carcinoma (HCC) remains a major challenge for clinicians and patients, and its progression may be related to hypoxia-inducible factor (HIF) and PD-L1. LW6 is a drug that inhibits hypoxia by reducing HIF-1α accumulation and gene transcriptional activity. However, its effect and regulatory mechanism in HCC remain to be revealed, especially under hypoxic conditions. The HIF-1α and PD-L1 expression in HCC specimens and paracarcinoma tissues was evaluated by a tissue microarray (TMA). The effects of LW6 were evaluated by cell viability, colony formation, and Transwell assays and xenografted nude mice. Cell cycle and apoptosis of HCC cells were detected by flow cytometry. The effects of LW6 on HIF-1α signaling and its targets PD-L1 and VEGF were evaluated through qRT-PCR, Western blots, Cell transfection, Transwell migration and invasion assays, immunohistochemistry, immunofluorescence and luciferase assays. In this study, we found that LW6 had antiproliferative effects on HCC and promoted HCC cell apoptosis, inhibited their migration and invasion, and affected their cell cycle. LW6 dramatically decreased HIF-1α expression through the VHL-dependent proteasome system pathway, inhibited HIF-1α transcriptional activation, and reduced PD-L1 expression by inhibiting EGFR pathway activation. These results suggest that LW6 can promote apoptosis of HCC cells by inhibiting HIF-1α, inhibit tumor angiogenesis, and downregulate the expression of PD-L1, which is an effective choice for the treatment of HCC. Moreover, inhibiting the hypoxic microenvironment combined with immunotherapy is expected to be a potentially effective strategy.

Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma.

Neural precursor cell expressed developmentally down-regulated 4-like protein (NEDD4L), an E3 ubiquitin ligase, exerts an important role in diverse biological processes including development, tumorigenesis, and tumor progression. Although the role of NEDD4L in the pathogenesis of lung adenocarcinoma (LUAD) has been described, the mechanism by which NEDD4L promotes LUAD progression remains poorly understood. In the study, the correlation between NEDD4L level and clinical outcome in LUAD patients was analysed using the data from The Cancer Genome Atlas (TCGA) database. NEDD4L expression in LUAD cell lines and tissue samples was assessed through quantitative real-time PCR (qRT-PCR). The biological function of NEDD4L on regulating LUAD cell proliferation was tested with Cell Counting Kit-8 (CCK-8) assay in vitro, and mouse xenograft tumor model in vivo. We found that NEDD4L expression was significantly decreased in LUAD tissues and cell lines. Lower expression of NEDD4L exhibited a significantly poorer overall survival. Functionally, NEDD4L knockdown in H1299 cells accelerated cell growth, whereas NEDD4L overexpression in A549 cells repressed cell proliferation. NEDD4L overexpression also inhibited tumor xenograft growth in vivo. Mechanistically, NEDD4L decreased the protein stability of notch receptor 2 (Notch2) through facilitating its ubiquitination and degradation by ubiquitin-proteasome system. Consequently, NEDD4L negatively regulated Notch signaling activation in LUAD cells, and RO4929097 (a Notch inhibitor) treatment effectively repressed the effect of NEDD4L knockdown on LUAD cell proliferation. Taken together, these results demonstrate that down-regulated NEDD4L facilitates LUAD progression by activating Notch signaling, and NEDD4L may be a promising target to treat LUAD.

Preparation and Comprehensive Properties of a High-Radiation-Shielding UHPC by Using Magnetite Fine Aggregate.

Nuclear technology benefits humans, but it also produces nuclear radiation that harms human health and the environment. Based on the modified Andreasen and Andersen particle packing model for achieving a densely compacted cementitious matrix, a new magnetite ultra-high-performance concrete (MUHPC) was designed using magnetite fine aggregate as a substitute for river sands with 0%, 20%, 40%, 60%, 80%, and 100% replacement ratios. The comprehensive properties of the developed MUHPC were tested and evaluated. These properties were fluidity, static and dynamic compressive strengths, high-temperature performance, antiradiation behaviors, hydration products, and micropore structures. Experimental results indicate that the developed MUHPC has high work performance and static and dynamic mechanical properties. The gamma ray shielding performance of MUHPC substantially improves with increased magnetite fine aggregate. Corresponding with 100% magnetite fine aggregate substitution, the linear attenuation coefficient of MUHPC is enhanced by 56.8% compared with that of ordinary concrete. Magnetite addition does not change the type of cement hydration products but improves the micropore structures of MUHPC and effectively reduces its total porosity and average pore diameter, thereby contributing to its mechanical and radiation shielding properties. The compressive strength and linear attenuation coefficient of the MUHPC can reach 150 MPa and 0.2 cm-1, respectively. In addition, the MUHPC also exhibits superior mechanical and radiation shielding performance at elevated temperatures (<400 °C). Finally, high strength and antiradiation performance support the use of MUHPC in radiation protection materials in the future.

miR-130b suppresses the invasion and migration of prostate cancer via inhibiting DLL1 and regulating the PI3K/Akt pathways.

Prostate cancer occurs in the prostatic epithelium and poses a threat to the health of middle-aged and older males. The objective of the present study was to explore the roles of microRNA (miRNA/miR)-130b in prostate cancer and potential molecular mechanisms in order to control the migration and invasion of prostate cancer. For this purpose, reverse transcription-PCR was performed to evaluate the mRNA levels of DLL1, phosphoinositide-3 kinase (PI3K), protein kinase B (Akt) and matrix metalloproteinase (MMP)9, and western blot analysis was carried out to detect the protein expression levels of DLL1, phosphorylated (p)-PI3K, p-Akt and MMP9. A Transwell assay was conducted to examine the invasion rate of prostate cancer cells. Furthermore, a scratch wound assay was performed to examine the migration rate of prostate cancer cells. A luciferase assay was performed to examine the interaction between miRNA and its target mRNA. The results revealed that miR-130b had abnormal (low) expression in tumor tissues compared with that in the adjacent normal tissue. An miR-130b mimic suppressed the expression of DLL1. The expression of p-PI3K, p-Akt and MMP9 in prostate cancer cells transfected with the miR-130b mimic was decreased in comparison to the negative control and control groups. Furthermore, migration and invasion were significantly suppressed in the miR-130b mimic group. In conclusion, a novel pathway interlinking miR-130b and MMP9, p-Akt and p-PI3K, which regulates the migration and invasion of prostate cancer cells, was identified. These findings provide an intriguing biomarker and treatment strategy for patients with prostate cancer.

Circ_0109291 Promotes Cisplatin Resistance of Oral Squamous Cell Carcinoma by Sponging miR-188-3p to Increase ABCB1 Expression.

Background: The occurrence of cisplatin (DDP) resistance in oral squamous cell carcinoma (OSCC) is a major challenge for OSCC treatment. Circular RNAs (circRNAs) have been associated with the development of cancer resistance, but the role of circ_0109291 in DDP resistance of OSCC is unclear. Methods: The expression of circ_0109291 and microRNA-188-3p (miR-188-3p) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit 8 (CCK8) assay, colony formation assay, and flow cytometry were performed to measure the DDP resistance, proliferation, and apoptosis of cells. The levels of apoptosis-related proteins and ATP-binding cassette sub-family B member 1 (ABCB1) protein were assessed via Western blot (WB) analysis. In addition, dual-luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull-down assay were used to illuminate the mechanism of circ_0109291. Animal experiments were employed to confirm the effect of circ_0109291 on OSCC tumor growth in vivo. Results: Circ_0109291 was higher expressed in DDP-resistant OSCC tissues and cells, and its knockdown suppressed proliferation and resistance and enhanced the apoptosis of OSCC cells. MiR-188-3p could be sponged by circ_0109291, and its overexpression had an inhibition effect on the DDP resistance of OSCC cells. ABCB1 was a target of miR-188-3p. Further experiments confirmed that both miR-188-3p inhibitor and ABCB1 overexpression also could invert the suppression effect of circ_0109291 silencing on the DDP resistance of OSCC cells. In vivo experiments revealed that silenced circ_0109291 could improve the sensitivity of the tumor to DDP. Conclusion: Circ_0109291 could promote the DDP resistance of OSCC, suggesting that silenced circ_0109291 might be a key step to inhibit OSCC resistance.

circKLHL24 Blocks Breast Cancer Development by Regulating the miR-1204/ALX4 Network.

Background: Breast cancer is a major challenge affecting women's survival. Circular RNAs have been demonstrated to be vital regulators in the pathogenesis of human cancers. The authors' objective was to determine the functional role and mechanism of circKLHL24 in breast cancer development. Materials and Methods: The expression of circKLHL24, miR-1204, and aristaless-like 4 (ALX4) mRNA was measured using quantitative real-time polymerase chain reaction. The effects on cell viability, proliferation, migration/invasion, and glycolysis were identified using the Cell Counting Kit-8 (CCK-8) assay, colony formation assay, Transwell assay, and glycolysis stress test, respectively. For glycolysis progression analysis, glucose consumption and lactate production were assessed using corresponding kits, and the expression of glycolysis-related proteins was detected by Western blot. The putative interactions between miR-1204 and circKLHL24 or ALX4 were validated by dual-luciferase reporter assay or RNA pull-down assay. The expression of ALX4 at the protein level was detected by Western blot. Animal study was performed to clarify the role of circKLHL24 in vivo. Results: circKLHL24 and ALX4 were downregulated, while miR-1204 was upregulated in breast cancer tissues and cells. circKLHL24 overexpression blocked cell viability, colony formation, migration/invasion, and glycolysis progression. circKLHL24 competitively targeted miR-1204, and miR-1204 reintroduction reversed the effects of circKLHL24 restoration. miR-1204 bound to ALX4, and circKLHL24 sponged miR-1204 to upregulate ALX4. Cell viability, colony formation, migration/invasion, and glycolysis progression suppressed by miR-1204 deficiency were recovered by ALX4 knockdown. Besides, circKLHL24 blocked tumor growth in vivo by regulating miR-1204 and ALX4. Conclusions: circKLHL24 blocked the progression of breast cancer by activating ALX4 through targeting miR-1204, which might be a novel perspective to understand the pathogenesis of breast cancer.

Real-world effectiveness and sensitivity of palbociclib plus endocrine therapy in HR+/HER2- patients with metastatic breast cancer.

ABSTRACT: Palbociclib has shown satisfactory outcomes when combined with endocrine therapy (ET) in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, data in Asia are currently scarce.This retrospective study aimed to evaluate the real-world effectiveness, sensitivity, and toxicity of palbociclib plus ET in HR+/HER2- MBC in North China. We recruited patients with HR+/HER2- MBC from August 2018 to July 2020 across 7 hospitals in North China. The primary endpoint was to evaluate progression-free survival (PFS) after initial progress on palbociclib therapy. The secondary endpoints included determining predictive biomarkers of palbociclib sensitivity and toxicity of palbociclib.A total of 54 patients were analyzed in this cohort with an estimated median follow-up time of 14.3 months. Patients who received palbociclib as a first-line treatment showed significantly prolonged PFS compared with those who received palbociclib as a second-line or beyond treatment (21.8 months vs 15.9 months vs 6.8 months) (P < .001). Besides, patients with Ki67 <30% (P = .024) and PR ≥20% (P = .041) in metastatic tumors had significantly longer PFS. The Cox proportional-hazards regression analyses proved that different lines (P = .001 in multivariate analysis), Ki67 <30% (P = .035 in multivariate analysis), and PR ≥20% (P = .045 in univariate analysis) in metastatic tumors affected PFS significantly. The most common adverse events were hematologic, with 31.48% of patients having neutropenia.Palbociclib plus ET significantly prolonged PFS for patients with HR+/HER2- MBC who received first-line therapy, with manageable toxicity. The values of Ki67 and PR in metastatic tumors may be potential predictive biomarkers of palbociclib sensitivity.

FAM49B promotes breast cancer proliferation, metastasis, and chemoresistance by stabilizing ELAVL1 protein and regulating downstream Rab10/TLR4 pathway.

BACKGROUND: Breast cancer (BC) is one of the most common cancers and the leading cause of death in women. Previous studies have demonstrated that FAM49B is implicated in several tumor progression, however, the role and mechanism of FAM49B in BC remain to be explored. Therefore, in this study, we aimed to systematically study the role of FAM49B in the proliferation, metastasis, apoptosis, and chemoresistance of BC, as well as the corresponding molecular mechanisms and downstream target. METHODS: The ONCOMINE databases and Kaplan-Meier plotter databases were analyzed to find FAM49B and its prognostic values in BC. FAM49B expression in BC and adjacent non-tumor tissues was detected by western blot and IHC. Kaplan-Meier analysis was used to identify the prognosis of BC patients. After FAM49B knockdown in MCF-7 and MDA-MB-231 cells, a combination of co-immunoprecipitation, MTT, migration, and apoptosis assays, nude mouse xenograft tumor model, in addition to microarray detection and data analysis was used for further mechanistic studies. RESULTS: In BC, the results showed that the expression level of FAM49B was significantly higher than that in normal breast tissue, and highly expression of FAM49B was significantly positively correlated with tumor volume, histological grade, lymph node metastasis rate, and poor prognosis. Knockdown of FAM49B inhibited the proliferation and migration of BC cells in vitro and in vivo. Microarray analysis revealed that the Toll-like receptor signaling pathway was inhibited upon FAM49B knockdown. In addition, the gene interaction network and downstream protein validation of FAM49B revealed that FAM49B positively regulates BC cell proliferation and migration by promoting the Rab10/TLR4 pathway. Furthermore, endogenous FAM49B interacted with ELAVL1 and positively regulated Rab10 and TLR4 expression by stabilizing ELAVL1. Moreover, mechanistic studies indicated that the lack of FAM49B expression in BC cells conferred more sensitivity to anthracycline and increased cell apoptosis by downregulating the ELAVL1/Rab10/TLR4/NF-κB signaling pathway. CONCLUSION: These results demonstrate that FAM49B functions as an oncogene in BC progression, and may provide a promising target for clinical diagnosis and therapy of BC.

Overweight with HBV infection limited the efficacy of TACE in hepatocellular carcinoma by inhibiting the upregulated HMGB1.

BACKGROUND: Transarterial chemoembolization (TACE) is an effective treatment for patients with hepatocellular carcinoma (HCC). However, the impact of hepatitis B viral (HBV) infection and body mass index (BMI) on TACE is controversial. The present study aimed to compare the influence of HBV and high BMI on TACE outcomes in advanced HCC. METHODS: Based on HBV infection history and BMI, patients were assigned to different subgroups. Blood samples were collected and analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. The primary endpoint was progression-free survival (PFS) and the overall survival (OS) in the population. RESULTS: Compared to overweight combined HBV patients who received TACE, people with normal weight or no viral infection had significantly better OS and PFS. Sex, age, portal vein tumor thrombus, BCLC, ECOG, and tumor diameter are the main risk factors affecting PFS and OS. Except for the postoperative fever, no significant difference was detected in adverse reactions. Irrespective of TACE, the average expression of HMGB1 in hepatitis or obesity patients was higher than that in normal individuals and did not show upregulation after TACE. Patients without overweight or HBV infection had a low expression of serum HMGB1 that was substantially upregulated after TACE. CONCLUSIONS: In this study, overweight combined HBV infection patients had shorter PFS and OS than other HCC patients. Thus, HBV and BMI maybe two factors affecting the efficacy of TACE via upregulated HMGB1.