The functional role of Pescadillo ribosomal biogenesis factor 1 in cancer.

Tumors are neogrowths formed by the growth of normal cells or tissues through complex mechanisms under the influence of many factors. The occurrence and development of tumors are affected by many factors. Pescadillo ribosomal biogenesis factor 1 (PES1) has been identified as a cancer-related gene. The study of these genes may open up new avenues for early diagnosis, treatment and prognosis of tumors. As a nucleolar protein and part of the Pes1/Bop1/WDR12 (PeBoW) complex, PES1 is involved in ribosome biogenesis and DNA replication. Many studies have shown that high expression of PES1 is often closely related to the occurrence, proliferation, invasion, metastasis, prognosis and sensitivity to chemotherapeutics of various human malignant tumors through a series of molecular mechanisms and signaling pathways. The molecules that regulate the expression of PES1 include microRNA (miRNA), circular RNA (circRNA), c-Jun, bromodomain-containing protein 4 (BRD4) and nucleolar phosphoprotein B23. However, the detailed pathogenic mechanisms of PES1 overexpression in human malignancies remains unclear. This article summarizes the role of PES1 in the carcinogenesis, prognosis and treatment of multiple tumors, and introduces the molecular mechanisms and signal transduction pathways related to PES1.

HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry.

Responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through binding of the viral spike protein (SARS-2-S) to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). Here we show that the high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitates ACE2-dependent entry of SARS-CoV-2. We find that the S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components to enhance viral uptake in vitro. SR-B1 expression facilitates SARS-CoV-2 entry into ACE2-expressing cells by augmenting virus attachment. Blockade of the cholesterol-binding site on SARS-2-S1 with a monoclonal antibody, or treatment of cultured cells with pharmacological SR-B1 antagonists, inhibits HDL-enhanced SARS-CoV-2 infection. We further show that SR-B1 is coexpressed with ACE2 in human pulmonary tissue and in several extrapulmonary tissues. Our findings reveal that SR-B1 acts as a host factor that promotes SARS-CoV-2 entry and may help explain viral tropism, identify a possible molecular connection between COVID-19 and lipoprotein metabolism, and highlight SR-B1 as a potential therapeutic target to interfere with SARS-CoV-2 infection.

Long Non-Coding RNA LEF1-AS1 Promotes Migration, Invasion and Metastasis of Colon Cancer Cells Through miR-30-5p/SOX9 Axis.

INTRODUCTION: Aberrant expression of long non-coding RNAs (lncRNAs) has been implicated in the tumorigenesis and progression of colon cancer. Lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1), a highly conserved and newly discovered long non-coding RNA, has been reported to be upregulated and correlated with poor prognosis in colon cancer, but the exact role of it remains uncertain. MATERIALS AND METHODS: In our study, the biological functions of LEF1-AS1 in colon cancer were analyzed by cell viability assay, colony formation assay, scratch wound healing assay, transwell cell invasion assay, soft agar assay, luciferase reporter assay, pull down assay, tumor xenograft model and Western blot. RESULTS: We found that LEF1-AS1 was upregulated in colon cancer patients and correlated with poor overall survival and recurrent-free survival. Besides, enforced expression of LEF1-AS1 in HT29 and T84 cells promoted migration, invasion, anchorage-independent growth, tumor xenograft formation and lung metastasis, while knockdown of LEF1-AS1 in COLO320 cells suppressed cell migration, invasion, anchorage-independent growth and tumor xenograft formation. In addition, LEF1-AS1 was directly interacted and inversely correlated with miR-30-5p in colon cancer, and SOX9 was a downstream target for miR-30-5p. LEF1-AS1 overexpression increased the expression level of SOX9, and restoration of SOX9 attenuated the effects caused by LEF1-AS1 knockdown in cell migration, invasion, anchorage-independent growth and tumor xenograft formation. CONCLUSION: Our results indicated that LEF1-AS1 promoted migration, invasion and metastasis of colon cancer cells partially through miR-30-5p/SOX9 axis. The oncogenic LEF1-AS1 could be a potential prognostic biomarker for colon cancer.

Nanocomplexes loaded with miR-128-3p for enhancing chemotherapy effect of colorectal cancer through dual-targeting silence the activity of PI3K/AKT and MEK/ERK pathway.

Although microRNAs (miRNAs)-based cancer therapy strategies have been proved to be efficient and superior to chemotherapeutic agents in certain extent, the unstable properties of miRNAs significantly impaired the wide application. Therefore, how to safely deliver the miRNAs to the targeted site of action is the most pivotal step to achieve the ideal treatment effect. In the present work, the miR-128-3p, which is able of inducing chromosomal instability, was loaded into the nanocomplexes developed by the PEG-PDMAEMA (PDMAEMA-NP). By this way, the miR-128-3p was shielded from exposure to various degrading enzymes in bloodstream. Additionally, the PEGylation endowed the PDMAEMA-NP with long time of circulation as demonstrated in vivo by pharmacokinetics investigation. To target and deliver the miR-128-3p to the site of action, a tumor-homing peptide CPKSNNGVC, which specifically targets the monocarboxylate transporter 1 (MCT1), was decorated on the surface of PDMAEMA-NP. Both in vitro and in vivo experiments demonstrated that more efficient delivery of miR-128-3p to cells or tumor tissues was obtained by the PDMAEMA-NP than plasmid. Additionally, modification of C peptides further enhanced the tumor accumulation of miR-128-3p, and in turn contributed to the stronger tumor growth inhibition effect. Underlying mechanisms study revealed that the miR-128-3p inhibited the growth, migration, and invasion of colorectal cancer (CRC) cells and progress of CRC tissues through silence of the activity of PI3K/AKT and MEK/ERK pathway. By this way, the chemotherapy effect of 5-Fluorouracil (5-Fu) was dramatically improved after co-treating the cells with miR-128-3p formulations.

The Mitochondrial Protein MAVS Stabilizes p53 to Suppress Tumorigenesis.

Recent reports have shown the critical role of the mitochondrial antiviral signaling (MAVS) protein in virus-induced apoptosis, but the involvement of MAVS in tumorigenesis is still poorly understood. Herein, we report that MAVS is a key regulator of p53 activation and is critical for protecting against tumorigenesis. We find that MAVS promotes p53-dependent cell death in response to DNA damage. MAVS interacts with p53 and mediates p53 mitochondrial recruitment under genotoxic stress. Mechanistically, MAVS inhibits p53 ubiquitination by blocking the formation of the p53-murine double-minute 2 (MDM2) complex, leading to the stabilization of p53. Notably, compared with their wild-type littermates, MAVS knockout mice display decreased resistance to azoxymethane (AOM) or AOM/dextran sulfate sodium salt (DSS)-induced colon cancer. MAVS expression is significantly downregulated in human colon cancer tissues. These results unveil roles for MAVS in DNA damage response and tumor suppression.

Comprehensive Analysis of Therapy-Related Messenger RNAs and Long Noncoding RNAs as Novel Biomarkers for Advanced Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common types of human cancers. However, the mechanisms underlying CRC progression remained elusive. This study identified differently expressed messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and small nucleolar RNAs (snoRNAs) between pre-therapeutic biopsies and post-therapeutic resections of locally advanced CRC by analyzing a public dataset, GSE94104. We identified 427 dysregulated mRNAs, 4 dysregulated lncRNAs, and 19 dysregulated snoRNAs between pre- and post-therapeutic locally advanced CRC samples. By constructing a protein-protein interaction network and co-expressing networks, we identified 10 key mRNAs, 4 key lncRNAs, and 7 key snoRNAs. Bioinformatics analysis showed therapy-related mRNAs were associated with nucleosome assembly, chromatin silencing at recombinant DNA, negative regulation of gene expression, and DNA replication. Therapy-related lncRNAs were associated with cell adhesion, extracellular matrix organization, angiogenesis, and sister chromatid cohesion. In addition, therapy-related snoRNAs were associated with DNA replication, nucleosome assembly, and telomere organization. We thought this study provided useful information for identifying novel biomarkers for CRC.

Sp1 contributes to overexpression of stanniocalcin 2 through regulation of promoter activity in colon adenocarcinoma.

BACKGROUND: Aberrant expression of stanniocalcin 2 (STC2) is implicated in colon adenocarcinoma (COAD). A previous study identified that STC2 functions as a tumor promoter to drive development of some cancers, but the role of its overexpression in the development of COAD remains unclear. AIM: To evaluate the regulation mechanism of STC2 overexpression in COAD. METHODS: The expression of STC2 in COAD was assessed by TCGA COAD database and GEO (GSE50760). Methylation level of the STC2 promoter was evaluated with beta value in UALCAN platform, and the correlation between STC2 expression and survival rate was investigated with TCGA COAD. Transcription binding site prediction was conducted by TRANSFAC and LASAGNA, and a luciferase reporter system was used to identify STC2 promoter activity in several cell lines, including HEK293T, NCM460, HT29, SW480, and HCT116. Western blotting was performed to evaluate the role of Sp1 on the expression of STC2. RESULTS: The central finding of this work is that STC2 is overexpressed in COAD tissues and positively correlated with poor prognosis. Importantly, the binding site of the transcription factor Sp1 is widely located in the promoter region of STC2. A luciferase reporter system was successfully constructed to analyze the transcription activity of STC2, and knocking down the expression of Sp1 significantly inhibited the transcription activity of STC2. Furthermore, inhibition of Sp1 remarkably decreased protein levels of STC2. CONCLUSION: Our data provide evidence that the transcription factor Sp1 is essential for the overexpression of STC2 in COAD through activation of promoter activity. Taken together, our finding provides new insights into the mechanism of oncogenic function of COAD by STC2.

Long noncoding RNA PURPL promotes cell proliferation in liver cancer by regulating p53.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) serve a key role in malignant transformation, tumor progression and metastasis. Increased expression of lncRNA p53 upregulated regulator of P53 levels (PURPL) has been reported to promote tumorigenicity in colorectal cancer; however, the role and potential mechanisms of PURPL in the development of liver cancer remain unclear. We employed reverse transcription­quantitative polymerase chain reaction to detect PURPL and p53 mRNA expression in liver cancer tissues and cell lines. Cell Counting Kit­8 and colony­forming assays were used to examine the cell proliferation; whereas, flow cytometry was applied to detect apoptosis and cell cycle progression. p53 expression was detected by western blotting. The results revealed that PURPL was significantly upregulated in liver cancer tissues compared with in paracancerous tissues, and was associated with tumor differentiation stage and tumor size. PURPL was also upregulated in various liver cancer cell lines. Silencing of PURPL inhibited liver cancer cells proliferation, blocked cell cycle progression, and promoted apoptosis. Most importantly, PURPL expression was negatively correlated with p53 mRNA expression. In summary, lncRNA­PURPL was proposed to promote cell proliferation in liver cancer by regulating the p53 gene. As such, it could serve as a potential therapeutic target for the diagnosis and treatment of liver cancer.

miR-142-3p Suppresses Cell Growth by Targeting CDK4 in Colorectal Cancer.

BACKGROUND/AIMS: Deregulation of microRNAs (miRNAs) has been associated with a variety of cancers, including colorectal cancer (CRC). Here, we investigated anomalous miR-142-3p expression and its possible functional consequences in primary CRC samples. METHODS: The expression of miR-142-3p was measured by quantitative RT-PCR in 116 primary CRC tissues and adjacent non-tumor tissues. The effect of miR-142-3p up- or down-regulation in CRC-derived cells was evaluated in vitro by cell viability and colony formation assays and in vivo by growth assays in xenografted nude mice. RESULTS: Using quantitative RT-PCR, we found that miR-142-3p was down-regulated in 78.4 % (91/116) of the primary CRC tissues tested when compared to the adjacent non-tumor tissues. We also found that the miR-142-3p mimic reduced in vitro cell viability and colony formation by inducing cell cycle arrest in CRC-derived cells, and inhibited in vivo tumor cell growth in xenografted nude mice. Inversely, we found that the miR-142-3p inhibitor increased the viability and colony forming capacity of CRC-derived cells and tumor cell growth in xenografted nude mice. In addition, we identified CDK4 as a potential target of miR-142-3p by predictions and dual-luciferase reporter assays. Concordantly, we found that miR-142-3p mimics and inhibitors could decrease and increase CDK4 protein levels in CRC-derived cells, respectively. CONCLUSION: From our results we conclude that miR-142-3p may act as a tumor suppressor in CRC and may serve as a tool for miRNA-based CRC therapy.

LncRNA BANCR promotes tumorigenesis and enhances adriamycin resistance in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy in the United States. Chemotherapeutic resistance is a massive obstacle for cancer treatment. The roles and molecular basis of long non-coding RNA BRAF-activated noncoding RNA (BANCR) in CRC progression and adriamycin (ADR) resistance have not been extensively identified. In this study, we found that BANCR and CSE1L expressions were upregulated in CRC tumor tissues. Meanwhile, CSE1L expression was correlated with depth of CRC. BANCR silencing suppressed cell proliferation and invasion capacity, increased apoptotic rate and potentiated cell sensitivity to ADR. CSE1L downregulation triggered a reduction of cell proliferation and invasion ability, and an increase of apoptosis rate and cell sensitivity to ADR. CSE1L overexpression attenuated si-BANCR-mediated anti-proliferation, anti-invasion and pro-apoptosis effects in CRC cells. BANCR acted as a molecular sponge of miR-203 to sequester miR-203 away from CSE1L in CRC cells, resulting in the upregulation of CSE1L expression. CSE1L knockdown inhibited expressions of DNA-repair-related proteins (53BP1 and FEN1) in HCT116 cells. BANCR knockdown also inhibited tumor growth and enhanced ADR sensitivity in CRC mice model. In conclusion, BANCR knockdown suppressed CRC progression and strengthened chemosensitization of CRC cells to ADR possibly by regulating miR-203/CSE1L axis, indicating that BANCR might be a promising target for CRC treatment.

Hsa_circ_0007534 as a blood-based marker for the diagnosis of colorectal cancer and its prognostic value.

BACKGROUND: Many studies have shown that differentially expressed circular RNA (circRNA) in plasma can serve as biomarkers in non-invasive detection of cancers during screening. However, the clinical significance of plasma circRNA in the diagnosis of colorectal cancer (CRC) is still not clear. Therefore, we examined expression of hsa_circ_0007534 in plasma to verify whether it can be utilized to diagnose and monitor CRC in routine clinical practice. METHODS: 112 CRC patients and 46 healthy controls were recruited to participate in our study. The levels of hsa_circ_0007534 in plasma samples and tumor tissues were identified by real-time quantitative polymerase chain reaction (RT-qPCR). The diagnostic value was evaluated using receiver operating characteristics (ROC) curves and the area under the ROC curves (AUC). The Kaplan-Meier survival curve was used to evaluate whether the expression level of hsa_circ_0007534 was associated with overall survival rate. RESULTS: Compared with the healthy control group, hsa_circ_0007534 expression was significantly increased in plasma from CRC patients. Increased hsa_circ_0007534 expression level in plasma was associated with progression of clinical classifications, metastatic phenotype, and poor differentiation in CRC patients. ROC analysis showed that hsa_circ_0007534 could distinguish CRC patients from healthy controls with high AUC (0.780), sensitivity (0.92) and specificity (0.522). Finally, high hsa_circ_0007534 expression was positively correlated with poor prognosis in CRC patients. CONCLUSION: All of the results suggest that hsa_circ_0007534 may be a potential cancer marker of patients with CRC and may associate with poor prognosis.

Long noncoding RNA PCAT-14 induces proliferation and invasion by hepatocellular carcinoma cells by inducing methylation of miR-372.

Long non-coding RNAs (lncRNAs) regulate oncogenesis by inducing methylation of CpG islands to silence target genes. Here we show that the lncRNA PCAT-14 is overexpressed in patients with hepatocellular carcinoma (HCC), and is associated with a poor prognosis after surgery. Our results demonstrate that PCAT-14 promotes proliferation, invasion, and cell cycle arrest in HCC cells. In addition, PCAT-14 inhibits miR-372 expression by inducing methylation of the miR-372 promoter. Simultaneously, miR-372 eliminates the effects of PCAT-14 on proliferation, invasion, and cell cycle in HCC cells. Moreover, PCAT-14 regulates expression of ATAD2 and activation of the Hedgehog pathway via miR-372. These findings indicate that PCAT-14 plays an important role in HCC, and may serve as a novel prognostic factor and therapeutic target.