First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

BACKGROUND: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). FINDINGS: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. INTERPRETATION: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. FUNDING: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

Effects of SMC1A on immune microenvironment and cancer stem cells in colon adenocarcinoma.

BACKGROUND: Our previous study suggested that SMC1 has significant functions in colorectal cancer (CRC). However, few reports have shown the effects of structural maintenance of chromosomes 1 (SMC1A) on the immune microenvironment and tumor stem cells. METHODS: The Cancer Genome Atlas (TCGA) database, CPTAC database, Human Protein Atlas (HPA) database, the Cancer Cell Line Encyclopedia (CCLE) and Tumor Immune Single-cell Hub were used. Flow cytometry and immunohistochemical analysis were checked for immune infiltration on MC38 mice model. Human CRC tissues were tested with RT-qPCR. RESULTS: The mRNA and protein levels of SMC1A were increased in colon adenocarcinoma (COAD) samples. SMC1A was associated with DNA activity. Interestingly, SMC1A was highly expressed in many types of immune cells at single-cell levels. Moreover, the high expression of SMC1A was positively correlated with immune infiltration, and immunohistochemical analysis showed that SMC1A was positively associated with CD45 expression in MC38 mice model. Also, the percentage of IL4+ CD4+ T cells (Th2) and FoxP3+ CD4+ T cells (Tregs) was significantly higher in the SMC1A overexpression group than in control by flow cytometry assay in vivo. SMC1A expression could affect the proliferation of T cells in the mice model. The mutation and somatic cell copy number variation (SCNV) of SMC1A were also associated with immune cell infiltration. In addition to SMC1A in the "hot" T-cell inflammatory microenvironment of colon cancer, SMC1A also positively correlates with the immune checkpoint genes CD274, CTLA4, and PDCD1 in colon adenocarcinoma (COAD) samples. Furthermore, we also found that SMC1A plays a positive correlation with the induction of cancer stem cells (CSCs). Our results also showed that miR-23b-3p binds SMC1A. CONCLUSION: SMC1A may be a bidirectional target switch that simultaneously regulates the immune microenvironment and tumor stem cells. Moreover, SMC1A may be a biomarker for the prediction of immune checkpoint inhibitor (ICI) therapy.

Evaluation of safety, effectiveness and treatment patterns of sodium zirconium cyclosilicate in management of hyperkalaemia in China: a real-world study protocol.

INTRODUCTION: Hyperkalaemia (HK) is a potentially life-threatening electrolyte imbalance associated with several adverse clinical outcomes. The efficacy and negative effects of currently existing treatment options have made HK management questionable. Sodium zirconium cyclosilicate (SZC), a novel highly selective potassium binder, is approved for the treatment of HK. The present study will be aimed to assess the safety, effectiveness and treatment patterns of SZC in Chinese patients with HK in a real-world clinical setting as it is required by China's drug review and approval process. METHODS AND ANALYSIS: This is a multicentre, prospective cohort study which plans to enrol 1000 patients taking SZC or willing to take SZC from approximately 40 sites in China. Patients ≥18 years of age at the time of signing the written informed consent and with documented serum potassium levels ≥5.0 mmol/L within 1 year before study enrolment day will be included. Eligible patients will receive SZC treatment and will be followed up for 6 months from enrolment day. The primary objective will be to evaluate the safety of SZC for the management of HK in Chinese patients in terms of adverse events (AEs), serious AEs as well as discontinuation of SZC. The secondary objectives will include understanding the SZC dosage information in terms of its effectiveness and treatment patterns under real-world clinical practice and assessing effectiveness of SZC during the observational period. ETHICS AND DISSEMINATION: This study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (approval number: YJ-JG-YW-2020). All the participating sites have received the ethics approval. Results will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05271266.

Developing Two Rapid Protein Extraction Methods Using Focused-Ultrasonication and Zirconia-Silica Beads for Filamentous Fungi Identification by MALDI-TOF MS.

Filamentous fungi identification by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been challenging due to the lack of simple and rapid protein extraction methods and insufficient species coverage in the database. In this study, we created two rapid protein extraction methods for filamentous fungi: a one-step zirconia-silica beads method (ZSB) and a focused-ultrasonication method (FUS). The identification accuracy of two methods were evaluated with the VITEK MS, as well as number of spectra peaks and signal-to-noise ratio (S/N) with M-Discover 100 MALDI-TOF MS compared to the routine method. The better method was applied to build a filamentous fungi in-house spectra library for the M-Discover 100 MS, and then another one and routine method were performed in parallel to verify the accuracy and commonality of the in-house library. Using the two optimized methods, the dedicated operating time before MALDI-TOF MS analysis was reduced from 30 min to 7 (ZSB) or 5 (FUS) min per sample, with only a few seconds added for each additional strain. And both two methods identified isolates from most mold types equal to or better than the routine method, and the total correct identification rate using VITEK MS was 79.67, 76.42, and 76.42%, respectively. On the other hand, the two rapid methods generally achieved higher maximum and minimum S/N ratios with these isolates tested as compared to the routine method. Besides, the ZSB method produced overall mean of maximum and minimum S/N ratio higher than that by FUS. An in-house library of M-Discover MS was successfully built from 135 isolates from 42 species belonging to 18 genera using the ZSB method. Analysis of 467 isolates resulted in 97.22% correctly identified isolates to the species level by the ZSB method versus 95.50% by the routine method. The two novel methods are time- and cost-effective and allow efficient identification of filamentous fungi while providing a simplified procedure to build an in-house library. Thus, more clinical laboratories may consider adopting MALDI-TOF MS for filamentous fungi identification in the future.

MiR-133a-3p attenuates resistance of non-small cell lung cancer cells to gefitinib by targeting SPAG5.

BACKGROUND: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), clinically used to treat patients with non-small cell lung cancer driven by EGFR mutations. Unfortunately, EGFR-TKI resistance has become a clinical problem for the effective treatment of NSCLC patients. The purpose of this study was to explore the effect and mechanism of miR-133a-3p on the gefitinib sensitivity of NSCLC cells. METHODS: The gefitinib-resistant PC9 (PC9/GR) cells were established through repeated long-term exposure to gefitinib for half a year. Then, PC9/GR cells were transfected with miR-133a-3p mimics and PC9 cells were transfected with miR-133a-3p inhibitors to increase or decrease the expression of miR-133a-3p. CCK-8 assay, colony formation assay, and caspase-3 activity assay were employed to detect cell resistance to gefitinib. Quantitative real-time PCR and Western blotting were used to evaluate the levels of miR-133a-3p, SPAG5, and other related genes. Starbase database was used to predict the target gene of miR-133a-3p and the prognosis of NSCLC patients. Target gene of miR-133a-3p was verified through dual-luciferase reporter gene assay. RESULTS: MiR-133a-3p was significantly downregulated in gefitinib-resistant cell line PC9/GR vs. gefitinib-sensitive cell line PC9. Overexpression of miR-133a-3p increased the sensitivity of NSCLC cells to gefitinib and vice versa. Furthermore, SPAG5 is an important target gene of miR-133a-3p, and SPAG5 can reverse miR-133a-3p-mediated gefitinib sensitivity of NSCLC cells. CONCLUSIONS: These findings indicated that miR-133a-3p/SPAG5 axis played a vital role in acquired resistance to gefitinib in NSCLC cells, and miR-133a-3p may represent a potential therapeutic strategy for the treatment of human NSCLC.

Roxadustat in treating anemia in dialysis patients (ROAD): protocol and rationale of a multicenter prospective observational cohort study.

BACKGROUND: Roxadustat has been shown effective in treating patients with anemia due to chronic kidney disease. However, its long-term effect on clinical outcomes and socioeconomic burden and safety remains unclear. METHODS/DESIGN: This is a multicenter, prospective, longitudinal observational cohort study assessing if Roxadustat improves prognosis in dialysis patients. Primary outcomes will be major adverse cardiovascular events (MACE), defined as composites of cardiovascular death, myocardial infarction, cerebral infarction, hospitalization because of heart failure; all-cause mortality, and annual economic costs in two years. The data will be collected via Research electronic data capture (REDCap) based database as well as software-based dialysis registry of Sichuan province. The primary outcomes for the ROAD study participants will be compared with those in the dialysis registry cohort. Data at baseline and study follow up will also be compared to assess the association between Roxadustat and long-term clinical outcomes. DISCUSSION: The main objective of this study is to the assess long-term association of Roxadustat on MACE, all-cause mortality, socio-economic burden, safety in dialysis patients, which will provide guidance for designing further large randomized controlled trials to investigate this clinic question. STUDY REGISTRATION: The study has been registered in Chinese Clinical Trials Registry (ROAD, ROxadustat in treating Anemia in Dialysis patients, registration number ChiCTR1900025765) and provincial observational cohort database (Renal disEAse observational CoHort database, REACH, ChiCTR1900024926), registered 07 September 2019, http://www.chictr.org.cn .

JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvß3 signaling.

Background: JWA gene is known to down-regulate SP1 and reduces the expression level of Integrin αvß3. Here, we identified a functional polypeptide (JP1) based on the active fragment of the JWA protein to suppress melanoma growth and metastasis by inhibiting the Integrin αvß3. Methods: We conducted a series of melanoma growth and metastasis mouse models to evaluate anti-melanoma effect of JP1 peptide. 18F-labeled JP1 (18F-NFP-JP1) was detected by Micro-PET assay to demonstrate drug biodistribution. Toxicity test in cynomolgus monkeys and pharmacokinetic studies in rats were done to assess the druggability. The expression of MEK1/2, NEDD4L, SP1 and Integrin αvß3 were detected in vitro and vivo models. Results: The peptide JP1 with the best anticancer effect was obtained. Micro-PET assay showed that JP1 specifically targeting to melanoma cells in vivo. JP1 inhibited melanoma growth, metastasis, and prolonged the survival of mouse. JP1 reduced the dosage and toxicity in combination with DTIC in melanoma xenograft and allograft mouse models. Cynomolgus monkey toxicity test showed no observed adverse effect level (NOAEL) of JP1 was 150 mg/kg. Mechanistically, JP1 was shown to activate p-MEK1/2 and triggered SP1 ubiquitination in melanoma cells. NEDD4L, an E3 ubiquitin ligase, was activated by p-MEK1/2 and to ubiquitinate SP1 at K685 site, resulting in subsequent degradation. Conclusions: JP1 was developed as a novel peptide that indicated therapeutic roles on proliferation and metastasis of melanoma through the NEDD4L-SP1-Integrin αvß3 signaling.

Effectiveness and Safety of Apatinib in Patients with Advanced or Metastatic Adenocarcinoma of Stomach or Gastroesophageal Junction: A Prospective Observation Study.

BACKGROUND: Apatinib showed promising efficacy in the treatment of advanced or metastatic gastric cancer (mGC) in previous clinical studies. However, the real-world data are limited, and this study aimed to assess the effectiveness and safety of apatinib for the treatment of advanced or mGC in this setting. METHODS: In this prospective observational study, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and treatment-related adverse events (AEs) were recorded and evaluated. Univariate and multivariate analyses were conducted to explore potential biomarkers which might be related to the effectiveness. RESULTS: A total of 321 mGC patients from 47 centers in China were enrolled between July 1, 2015, and March 1, 2018. Thirty-two patients achieved partial response, 155 patients achieved stable disease, and 115 patients had progressive disease, and no CR was achieved, illustrating an ORR of 10.60% and a DCR of 61.92%. The median PFS and OS were 4.0 and 8.2 months, respectively. Multivariate Cox analysis showed that the potential biomarkers associated with longer PFS were combination regimens plus taxel/docetaxel, and apatinib initial dosage ≥500mg, occurrence of AEs of leukopenia, and hand-foot syndrome. Main AEs were proteinuria (17.1%), hypertension (15.9%), and handfoot syndrome (8.7%). CONCLUSION: The present prospective observational study showed favorable effectiveness and safety of apatinib in real-world patients with advanced or metastatic GC in China. (A prospective, multi-center, non-intervention study of apatinib in the treatment of advanced gastric cancer-Trial Registry Number: ChiCTR-OPN-15006601).

JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25/SP1/MMP2 axis.

BACKGROUND: Gastric cancer (GC) is the most prevalent gastrointestinal tumor with an unfavorable clinical prognosis. GC patients are largely threatened owing to metastasis and drug resistance. Tumor angiogenesis plays an important role in the development of gastric cancer and is a challenge in the treatment of gastric cancer. METHODS: Mouse xenograft models were used for screening of therapeutic peptides on GC growth and metastasis. Routine laboratory experimental methods including conditional cell culture, tube formation assay, qRT-PCR, Western blotting, immunohistochemistry (IHC), ubiquitination assay, and immunofluorescence (IF) were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3/SP1 and TRIM25/MEK1/2. RESULTS: We identified an MMP2-targeted peptide JP3 that plays inhibiting roles in modulating growth and metastasis of GC in vivo and has no observable toxic side effects. JP3 reduced tumor microvessel density (MVD) in vivo and human umbilical vein endothelial cells (HUVECs) tube formation in vitro. Mechanistic studies revealed that JP3 reduces polyubiquitination-mediated degradation of TRIM25 by increasing the stability of TRIM25 through phosphorylating it at Ser12. TRIM25, as an E3 ubiquitin ligase, promoted the ubiquitin of SP1 at K610, further suppressed expression of MMP2 and inhibited angiogenesis in GC. Importantly, the inversely association between TRIM25 and SP1 protein level was further verified in human GC tissues. Decreased TRIM25 expression and increased SP1 expression in tumor tissues were positively correlated with poor prognosis of GC patients. CONCLUSIONS: MMP2-targeted peptide JP3 plays a therapeutic role in GC through anti-angiogenesis by modulating TRIM25/SP1/MMP2.

Fosaprepitant versus aprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy: a multicenter, randomized, double-blind, double-simulated, positive-controlled phase III trial.

BACKGROUND: To establish the role of antiemetic therapy with neurokinin-1 (NK-1) receptor antagonists (RAs) in Chinese patients associated with cisplatin-base chemotherapy regimens, this study evaluated the efficacy and safety of single-dose intravenous fosaprepitant-based triple antiemetic regimen to a 3-day orally aprepitant-based antiemetic triplet schedule for the prevention of chemotherapy-induced nausea and vomiting (CINV). METHODS: A randomized, double-blind, positive-control design was used to test the noninferiority of fosaprepitant towards aprepitant. Patients receiving cisplatin-base (≥50 mg/m2) chemotherapy were administrated palonosetron and dexamethasone with a single-dose fosaprepitant (150 mg on day 1) or a standard aprepitant regimen (125 mg on day 1, 80 mg on day 2 and day 3). The primary endpoint was complete response (CR) during overall phase (OP). Secondary endpoints include CR during acute phase (AP) and delayed phase (DP), no vomiting and no significant nausea during OP, AP and DP. Accrual of 324 patients per treatment arm was planned to confirm noninferiority with expected CR of 75% and noninferiority margin of minus 10 percentage points. RESULTS: A total of 648 patients were randomly assigned, and 644 were evaluable for efficacy and safety. Antiemetic efficacy of CR during the OP with fosaprepitant and aprepitant was equivalent (71.96% versus 69.35%, P=0.4894). And a between-group difference of 2.61 percentage points was finally achieved (95% CI, -4.42 to 9.64) within predefined bounds for noninferiority (primary end point achieved). Both regimens were well tolerated and commonly reported adverse events (≥1%) were similar between these two group. CONCLUSIONS: Single-dose intravenous fosaprepitant (150 mg) combined with palonosetron and dexamethasone was well tolerated and demonstrated noninferior control of CINV to aprepitant-based triple regimen in Chinese patients treating with cisplatin-base chemotherapy.

Potential value of serum Aspergillus IgG antibody detection in the diagnosis of invasive and chronic pulmonary aspergillosis in non-agranulocytic patients.

BACKGROUND: At present, serum Aspergillus IgG and IgM antibody detection is mainly used in the diagnosis of chronic pulmonary aspergillosis (CPA), but its value in the diagnosis of invasive pulmonary aspergillosis (IPA) in non-agranulocytic patients is still unclear. IgM can be used as a marker of acute infection to help diagnose acute infection-related diseases. IgG is a marker of long-term infection and is used to assist in the diagnosis of pre-existing or chronic infection-related diseases. The aim of this study was to investigate and compare the value of serum Aspergillus IgG and IgM antibody detection in the diagnosis of IPA and CPA in non-agranulocytic patients. METHODS: Fifty-eight cases of pulmonary aspergillosis (37 IPA and 21 CPA cases), 15 cases of community-acquired bacterial pneumonia and 50 cases in the healthy control group were collected. The serum (1,3)-ß-D-glucan test (G test) was performed with a chromogenic method, and the galactomannan test (GM test) and Aspergillus IgG and IgM antibody detection were performed by commercial enzyme-linked immunosorbent assay (ELISA) in all patients. The sensitivity and specificity, cut-off value and area under the curve (AUC) of Aspergillus IgG and IgM antibodies were further obtained by receiver operating characteristic (ROC) curves. RESULTS: The positive rate of the G test, Aspergillus IgG antibody detection and the GM test also showed notable differences among the IPA, CPA, community-acquired bacterial pneumonia and healthy groups (P = 0.006, P <  0.001 and P = 0.217, respectively). Only the positive rate of the GM test showed a significant difference between the IPA and CPA groups (P = 0.04). ROC curves indicated that Aspergillus IgG antibody detection had a higher specificity in the IPA group than in the CPA group (0.952). The detection of Aspergillus IgG antibody can preferably distinguish IPA from community-acquired bacterial pneumonia and healthy controls (sensitivity = 0.923, specificity = 0.459, cut-off value = 134.46, AUC = 0.727). It can also distinguish CPA from community-acquired bacterial pneumonia and healthy controls (sensitivity = 0.952, specificity = 0.692, cut-off value = 75.46, AUC = 0.873). CONCLUSIONS: Serum Aspergillus IgG antibody detection may have certain clinical value in the diagnosis of IPA and CPA in non-agranulocytic patients.

Cancer-associated fibroblasts promote cell growth by activating ERK5/PD-L1 signaling axis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most common diseases, accounting for about 10 % cancer-related deaths. Previous studies have found that caner-associated fibroblasts (CAFs) are closely related to the occurrence and metastasis of CRC, but the detailed mechanism is not precise. METHODS: Tumor cells and fibroblasts were co-cultured with a transwell system. Cell Counting Kit-8 and colony formation assays were performed to test the ability of cell proliferation. The flow cytometry was used to detect cell apoptosis. Western Blot was performed to assess protein expression levels. Quantitative real-time PCR was performed to detect mRNA expression levels. ERK5-IN-1 was used to inhibit the autophosphorylation of ERK5. RESULTS: CAFs promoted cell proliferation and inhibited cell apoptosis in CRC cells. CAFs promoted the phosphorylation of ERK5 and the expression of programmed death-ligand 1 (PD-L1). Activated ERK5 promotes cell proliferation and inhibited cell apoptosis in CRC cells. The expression levels of ERK5 correlated with the expression of PD-L1 in CRC cells. CAFs promote cell growth by activating the ERK5/PD-L1 signaling axis in colorectal cancer. CONCLUSIONS: CAFs significantly promoted cell proliferation and inhibited cell apoptosis in CRC cells, which features are dependent on regulating the ERK5/PD-L1 signaling axis.

Aptamer-conjugated and doxorubicin-loaded grapefruit-derived nanovectors for targeted therapy against HER2+ breast cancer.

Increased human epidermal growth factor receptor 2 (HER2) expression is a hallmark of HER2+ breast cancer. HER2 promotes the growth of cancer cells and makes them particularly aggressive. Currently, trastuzumab is the only HER2-targeted therapeutic agent approved by the FDA for HER2-overexpressing breast cancer treatment. However, clinical efficacy of trastuzumab is limited greatly by the occurrence of drug resistance. In this study, an aptamer (HA1) specific for HER2-overexpressing breast cancer cells was selected using Cell-SELEX. This allowed the development of grapefruit-derived nanovectors (GNVs) conjugated with HA1 that targeted specifically HER2+ breast cancer cells. In vitro experiments demonstrated that HA1 effectively promoted the internalisation of GNVs into cancer cells and tumour spheroids. In vivo data showed that drug delivery to tumour tissues and antitumor activities were dramatically enhanced by conjugating HA1 with drug-loaded GNVs. This study indicates that aptamers mediating targeted drug delivery by GNVs represent a promising strategy for HER2+ breast cancer therapy.

SMC1 promotes proliferation and inhibits apoptosis through the NF­κB signaling pathway in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer­associated mortality globally. Increasing evidence has indicated that structural maintenance of chromosomes 1 (SMC1) may serve an important role in solid tumors as a tumor enhancer. In the present study, it was identified via reverse transcription­quantitative PCR and western blot analyses that expression of SMC1 was significantly upregulated in CRC cell lines (SW480, HCT­116 and SW620) compared with NCM460 normal epithelial cells. To determine the potential involvement of SMC1 in the malignant phenotypes of CRC cells, SMC1 was knocked down in SW620 cells and SMC1 was overexpressed in SW480 cells in vitro. As a result, cell viability, proliferation, invasion and migration were suppressed in transduced SW620 cells but enhanced in SW480 cells, as determined using MTT, colony formation and Transwell assays; conversely, flow cytometric analysis revealed that cell apoptosis was increased in SW620 cells and inhibited in SW480 cells following lentiviral infection. In addition, an in vivo mouse xenograft model revealed that knocking down SMC1 suppressed tumor growth and increased apoptosis; however, overexpressing SMC1 enhanced tumor growth and suppressed apoptosis. Further experiments demonstrated that the role of SMC1 on CRC may involve downregulation of the NF­κB­associated signaling pathway. Finally, the present data from clinical CRC tumor samples showed that increased expression of SMC1 was significantly associated with distant metastasis, higher TNM stage, primary tumor size, lymph node metastasis and worse overall survival. Collectively, the present results suggested that SMC1 served an important role in the development of CRC and may be a predictive prognostic biomarker in patients with CRC.

Circular RNA hsa_circ_0007142 Is Upregulated and Targets miR-103a-2-5p in Colorectal Cancer.

Circular RNAs (circRNAs) are a large class of endogenous noncoding RNAs that regulate gene expression and mainly function as microRNA sponges. This study aimed to explore the aberrant expression of circRNAs in colorectal cancer (CRC). Using a circRNA microarray, we identified 892 differentially expressed circRNAs between six pairs of CRC and adjacent paracancerous tissues. Among them, hsa_circ_0007142 was significantly upregulated. Further analysis in 50 CRC clinical samples revealed that hsa_circ_0007142 upregulation was associated with poor differentiation and lymphatic metastasis of CRC. Bioinformatic analysis and luciferase reporter assay showed that hsa_circ_0007142 targeted miR-103a-2-5p in CRC cells. Moreover, the silencing of hsa_circ_0007142 by siRNAs decreased the proliferation, migration, and invasion of HT-29 and HCT-116 cells. Taken together, these findings suggest that hsa_circ_0007142 is upregulated in CRC and targets miR-103a-2-5p to promote CRC.

circCTIC1 promotes the self-renewal of colon TICs through BPTF-dependent c-Myc expression.

Colon tumor is a conman tumor in the world. There are various kinds of cells in colon tumor bulk, and only a small population can initiate tumor efficiently and termed as tumor-initiating cells (TICs). With self-renewal and differentiation capacities, colon TICs drive colon tumorigenesis, metastasis and relapse. However, the molecular mechanisms of colon TICs self-renewal are elusive. Here, we found that circular RNA (circCTIC1) was highly expressed in colon tumor and colon TICs. circCTIC1 knockdown impaired the self-renewal of colon TICs, and its overexpression played an opposite role. circCTIC1 promoted the expression of c-Myc and drove the self-renewal of colon TIC through c-Myc-dependent manner. circCTIC1 interacted with nuclear remodeling factor (NURF) complex, recruited NURF complex onto c-Myc promoter and finally drove the transcriptional initiation of c-Myc. Altogether, circCTIC1 drove the self-renewal of colon TICs through bromodomain PHD finger transcription factor (BPTF)-mediated c-Myc expression.

MicroRNA-371a-3p promotes progression of gastric cancer by targeting TOB1.

An integrated study was conducted to identify the potential prognosis biomarker of the gastric cancer. The study analyzed the expression level of microRNAs (miRNAs) and clinical follow-up information of gastric cancer patients. miR-371-3p was determined as a promising biomarker for the prognosis of GCs among the 74 dysregulated miRNAs examined. The qRT-PCR analysis of the expression of miR-371-3p in 121 GC tumors confirmed its overexpression and correlation with aggravation of the GC patients. The in vitro functional assays demonstrated that overexpression of miR-371-3p promoted proliferation, colony formation, migration and invasion of the GC cells, whereas miR-371-3p depletion led to the opposite. The findings were further confirmed by the in vivo knockdown of miR-371-3p experiment: the depletion of miR-371-3p inhibited tumor growth and metastasis. Based on the results of the bioinformatics analysis and bioassays, TOB1 was found to be the direct target of miR-371-3p, functioning as a tumor suppressor in GC cells. TOB1 was prerequisite for miR-371-3p to promote cell proliferation and migration. In conclusion, the results suggest that miR-371-3p is a potential prognosis biomarker and therapeutic target for GC.

LncRNA FOXD2-AS1 Regulates miR-25-3p/Sema4c Axis To Promote The Invasion And Migration Of Colorectal Cancer Cells.

PURPOSE: Although the roles of lncRNA FOXD2-AS1 have been investigated in many types of cancers including colorectal cancer (CRC), its functionality remains to be further investigated. Analysis of the TCGA data set revealed that FOXD2-AS1 was up-regulated in CRC tissues. This study aimed to analyze the function of FOXD2-AS1 in CRC. METHODS: FOXD2-AS1 expression was detected by qPCR. A 5-year follow-up study was performed to analyze the prognostic value of FOXD2-AS1 for CRC. Overexpression experiments were performed to analyze the interactions among FOXD2-AS1, miR-25-3p and Sema4C. Transwell assays were performed to analyze cell invasion and migration. RESULTS: In this study, we further confirmed the up-regulation of FOXD2-AS1 in CRC patients and showed that high FOXD2-AS1 level predicted poor survival. Bioinformatics analysis showed that miR-25-3p may bind FOXD2-AS1, while over-expression experiments showed no effects on each other's expression. Instead, FOXD2-AS1 over-expression led to the up-regulate Sema4C, which is a target of miR-25-3p. Transwell assay showed that FOXD2-AS1 and Sema4C over-expression led to the increased invasion and migration rates of CRC cells. MiR-25-3p plays the opposite role and attenuated the effects of FOXD2-AS1 and Sema4C over-expression. CONCLUSION: FOXD2-AS1 may regulate the miR-25-3p/Sema4C axis to promote the invasion and migration of CRC cells.

Correction to: Effect of long non-coding RNA Gas5 on proliferation, migration, invasion and apoptosis of colorectal cancer HT-29 cell line.

[This corrects the article DOI: 10.1186/s12935-017-0478-7.].

Effect of long non-coding RNA Gas5 on proliferation, migration, invasion and apoptosis of colorectal cancer HT-29 cell line.

Objective: This study aims to investigate the effect of long non-coding RNA (lncRNA) Gas5 on proliferation, migration, invasion and apoptosis of colorectal cancer (CRC) HT-29 cell line. Methods: CRC and normal tissues were collected and prepared from a total of 126 CRC patients, and normal intestinal epithelial cell line FHC and CRC cell lines (HCT-8, HT-29, HCT-116 and SW-480) were prepared. Gas5 expression was detected by quantitative reverse transcriptase-polymerase chain reaction. HT-29 cell line exhibiting the lowest Gas5 expression was selected for further experimentation and divided into blank, negative control and pcNDA-Gas5 groups. The cell counting kit-8 assay was used to test cell proliferation. Flow cytometry was applied to examine cell apoptosis. Transwell assay was performed to detect the migration and invasion of HT-29 cells. The mRNA and protein expression of factors in the classical proliferation (Akt/Erk) and apoptosis (caspase-9/caspase-3) pathways were detected. Results: Gas5 expression was lower in CRC tissues compared to the adjacent normal tissues, and is also lower in CRC cell lines than FHC cell line. Gas5 expression was associated with tumor size and TNM staging. Gas5 expression, distant metastasis, tumor differentiation and TNM staging were independent CRC prognostic factors. The results showed that elevated Gas5 expression inhibited proliferation, migration and invasion, but promoted apoptosis of CRC cells. Meanwhile, elevated Gas5 expression inhibited mRNA expression of Akt and Erk and protein expression of p-Akt and p-Erk, which promoted Casp9 mRNA and pho-Casp9 protein expression but inhibited Casp3 mRNA and pho-Casp3 protein expression. Conclusion: The findings indicated that overexpression of lncRNA Gas5 can inhibit the proliferation, migration and invasion but promote apoptosis of CRC cells.