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Inhibition of cytosolic phospholipase A2 alpha increases chemosensitivity in cervical carcinoma through suppressing -catenin signaling

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (6)

Cytosolic phospholipase A2alpha (cPLA2) is a key mediator of tumorigenesis. In this study, by using a combination of pharmacological and genetic approaches in cell models and patient samples, we identify cPLA2 as a selective target to increase chemosensitivity in cervical cancer. We found that transcript and protein levels of cPLA2 but not other forms of cPLA2 (e.g., cPLA2 and cPLA2) were consistently increased in all tested malignant cervical cancer cells and tissues compared to normal counterparts, suggesting that cPLA2 upregulation is a common feature in cervical cancer. We further found that promoting growth and survival rather than invasion were the predominant roles of cPLA2 on cervical cancer. In addition, chemotherapeutic agents achieved similar to 100% inhibition efficacy in cPLA2-depleted cervical cancer cells, demonstrating the important role of cPLA2 in chemoresistance. Importantly, we identify that -catenin is critically involved in the molecular mechanism of cPLA2's action in cervical cancer. In summary, our work demonstrates the multiple essential roles of cPLA2 in cervical cancer, particularly in chemoresistance, via a -catenin-dependent manner. Our work also suggests that targeting cPLA2 has a therapeutic value in overcoming chemoresistance in cervical cancer or other cPLA2-regulated cancers.

IF:2.88

MicroRNA-23a depletion promotes apoptosis of ovarian cancer stem cell and inhibits cell migration by targeting DLG2

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (6)

Ovarian cancer (OC) is xenogeneic that is influenced by many generated factors related to epigenetic factors to accelerate tumor metastasis. This study was conducted with the objective of investigating the effect of microRNA-23a-3p (miR-23a) on the biological characteristics of OC stem cells by targeting discs large homolog 2 (DLG2). OC-related differentially expressed genes were screened by microarray-based gene expression analysis, after which a list of miRNAs that regulate the genes was predicted. In total, 50 patients diagnosed with OC were enrolled in this study. DLG2 positive protein expression was measured in OC tissues. The interaction between DLG2 and miR-23a was predicted and analyzed through luciferase activity measurement. With the intervention of miR-23a and/or DLG2 expression in OC stem cells, the expression of miR-23a, DLG2, Bax, Bcl-2, Oct-4, and Nanog was determined. Afterward, different cell experiments were conducted to examine the regulation effect of miR-23a in OC stem cells. Tumor formation in vivo was also evaluated in nude mice. DLG2 had low expression in OC. The results showed that there was a decrease in the expression of Bcl-2, Oct-4, and Nanog, while DLG2 and Bax were increased as a result of miR-23a depletion. In addition, when miR-23a was suppressed, cell viability, migration, invasion, cloning, and renewal abilities of OC stem cells were decreased, while apoptosis ability was enhanced. As a target gene of miR-23a, DLG2 downregulation reversed the suppressive function of miR-23a in the inhibition of OC development. Finally, in vivo experiment verified that miR-23a downregulation restrained the tumor growth in OC stem cells. In conclusion, our findings suggested that the inhibition of miR-23a results in the suppression of OC progression by releasing DLG2, which provides new understanding on the potential therapeutic effect of miR-23a inhibition in OC patients.

IF:2.88

KCNQ1OT1/miR-217/ZEB1 feedback loop facilitates cell migration and epithelial-mesenchymal transition in colorectal cancer

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (6)

Long noncoding RNAs are widely acknowledged as a group of regulatory factors in various diseases, especially in cancers. KCNQ1 overlapping transcript 1 (KCNQ1OT1) has been reported as oncogene in human cancers. However, the role of KCNQ1OT1 in colorectal cancer (CRC) has not been fully explained. Based on the database analysis, KCNQ1OT1 was highly expressed in CRC samples and predicted the poor prognosis for CRC patients. Functional experiments revealed that KCNQ1OT1 knockdown negatively affected the proliferation, migration and epithelial-mesenchymal transition (EMT) in CRC cells. Moreover, we identified the cytoplasmic localization of KCNQ1OT1 in CRC cells, indicating the post-transcriptional regulation of KCNQ1OT1 on gene expression. Mechanism experiments including RNA Immunoprecipitation (RIP) assay and dual luciferase reporter assays verified that KCNQ1OT1 acted as a competing endogenous RNA (ceRNA) in CRC by sponging microRNA-217 (miR-217) to up-regulate the expression of zinc finger E-box binding homeobox 1 (ZEB1). Further mechanism investigation revealed that ZEB1 enhanced the transcription activity of KCNQ1OT1 by acting as a transcription activator. Finally, rescue assays were designed to demonstrate the effect of KCNQ1OT1-miR-217-ZEB1 feedback loop on proliferation, migration, and EMT of CRC cells. In brief, our research findings revealed that ZEB1-induced upregulation of KCNQ1OT1 improved the proliferation, migration and EMT formation of CRC cells via regulation of miR-217/ZEB1 axis.

IF:2.88

Activation of CD3(+) T cells by Helicobacter pylori DNA vaccines in potential immunotherapy of gastric carcinoma

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (6)

Most of gastric carcinoma (GC) is attributed to infection by Helicobacter pylori (H. pylori) but there is increasing evidence that the positive H. pylori status correlates with better prognosis in GC. The H. pylori-induced cellular immune response may suppress cancer and in this work, recombinant pcDNA3 plasmids encoding various fragments of H. pylori virulence genes of cagA, vacA and babA are constructed and combined into groups to immunize BALB/c mice. The activated splenic CD3(+) T cells are purified and the anticancer effects are investigated in vitro and in vivo. The H. pylori DNA vaccines induce a shift in the response from Th1 to Th2 that mimicks the immune status in patients of GC with chronic H. pylori infection. The stimulated CD3(+) T cells inhibit the growth of human GC cells in vitro and adoptive transfusions of the CD3(+) T cells suppress the growth of GC xenograft in vivo. The effects may be caused by the larger ratios of infiltrated CD8(+)/CD4(+) T cells, reduced infiltration of regulatory FOXP3(+) T cells, and enhanced apoptosis induced by upregulation of Caspase-9/Caspase-3 and downregulation of Survivin. Our results reveal the potential immunotherapeutic value of H. pylori vaccine-activated CD3(+) T cells in those with advanced GC.

IF:2.88

Clinical importance of FANCD2, BRIP1, BRCA1, BRCA2 and FANCF expression in ovarian carcinomas

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (6)

Objective: DNA repair pathways are potential targets of molecular therapy in cancer patients. The FANCD2, BRIP1, BRCA1/2, and FANCF genes are involved in homologous recombination DNA repair, which implicates their possible role in cell response to DNA-damaging agents. We evaluated a clinical significance of pre-treatment expression of these genes at mRNA level in 99 primary, advanced-stage ovarian carcinomas from patients, who later received taxane-platinum (TP) or platinum-cyclophosphamide (PC) treatment.Methods: Gene expression was determined with the use of Real-Time PCR. The BRCA2 and BRIP1 gene sequence was investigated with the use of SSCP, dHPLC, and PCR-sequencing.Results: Increased FANCD2 expression occurred to be a negative prognostic factor for all patients (PC+TP:HR 3.85, p = 0.0003 for the risk of recurrence; HR 1.96, p = 0.02 for the risk of death), and this association was even stronger in the TP-treated group (HR 6.7, p = 0.0002 and HR 2.33, p = 0.01, respectively). Elevated BRIP1 expression was the only unfavorable molecular factor in the PC-treated patients (HR 8.37, p = 0.02 for the risk of recurrence). Additionally, an increased FANCD2 and BRCA1/2 expression levels were associated with poor ovarian cancer outcome in either TP53-positive or -negative subgroups of the TP-treated patients, however these groups were small. Sequence analysis identified one protein truncating variant (1/99) in BRCA2 and no mutations (0/56) in BRIP1.Conclusions: Our study shows for the first time that FANCD2 overexpression is a strong negative prognostic factor in ovarian cancer, particularly in patients treated with TP regimen. Moreover, increased mRNA level of the BRIP1 is a negative prognostic factor in the PC-treated patients. Next, changes in the BRCA2 and BRIP1 genes are rare and together with other analyzed FA genes considered as homologous recombination deficiency may not affect the expression level of analyzed genes.

IF:2.88

Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (7)

Pharmacological inhibition of PARP is a promising approach in treating high grade serous ovarian carcinoma (HGSOC). PARP inhibitors (PARPi) are most active in patients with defects in DNA damage repair (DDR) mechanisms, such as alterations in expression/function of DNA repair and homologous recombination (HR) genes/proteins, including BRCA1 and BRCA2. Benefit of PARPi could be extended towards HR-proficient patients by combining PARPi with agents that functionally abrogate HR. An attractive molecular target for this purpose is heat shock protein 90 (HSP90), which mediates the maturation and stability of several key proteins required for DDR. Here, we tested the hypothesis that targeted inhibition of HSP90 with a small-molecule inhibitor ganetespib would sensitize non-BRCA mutant ovarian carcinoma (OC) cells to PARP inhibition by talazoparib. We used commercially available cell lines, along with several novel HGSOC OC cell lines established in our laboratory. Ganetespib treatment destabilized HSP90 client proteins involved in DNA damage response and cell cycle checkpoint, and disrupted gamma-irradiation-induced DNA repair. The effects of the combination of ganetespib and talazoparib on OC cell viability and survival were also analyzed, and among the non-BRCA mutant cell lines analyzed, the combination was synergistic in several cell lines (OVCAR-3, OC-1, OC-16). Together, our data suggest that ganetespib-mediated inhibition of HSP90 effectively disrupts critical DDR pathway proteins and may sensitize OC cells without 'BRCAness' to PARPi. From a clinical perspective, this suggests that HSP90 inhibition has the potential to sensitize some HGSOC patients without HR pathway alterations to PARPi, and potentially other DNA-damage inducing agents.

IF:2.88

Antitumor properties of triptolide: phenotype regulation of macrophage differentiation

期刊: CANCER BIOLOGY & THERAPY, 0; ()

Tumor-associated macrophages (TAMs), which generally exhibit an M2-like phenotype, play a critical role in tumor development. Triptolide exerts a unique bioactive spectrum of anticancer activities. The aim of this study was to determine whether triptolide has any effect on the activation of TAMs and the production of tumor-promoting mediators. ICR-1 mice with azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors and BALB/c mice co-inoculated with 4T1 cells and M2-polarized RAW264.7 cells were used to examine whether the inhibitory effect of triptolide on tumor progression was mediated by the targeting of TAMs. Real-time PCR, Western blot, immunofluorescence staining, and flow cytometry assays were performed to determine the expression of cell surface markers and cytokine production. The results showed that triptolide inhibited macrophage differentiation toward the M2 phenotype and abolished M2 macrophage-mediated tumor progression. Furthermore, triptolide inhibited the expression of M2 markers, such as CD206, Arginase 1, and CD204, and inhibited the secretion of anti-inflammatory cytokines. Thus our study indicated that triptolide selectively inhibited the functions of M2-polarized macrophages and TAMs, and this inhibitory effect of triptolide on TAM viability, differentiation, and cytokine production might elucidate the major mechanisms underlying its antitumor activity. Our findings provide important information for the potential clinical application of triptolide in cancer therapy.

Low pretreatment lymphocyte/monocyte ratio is associated with the better efficacy of neoadjuvant chemotherapy in breast cancer patients

期刊: CANCER BIOLOGY & THERAPY, 0; ()

The combination of some parameters, including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and neutrophil to monocyte ratio (NMR), which are associated with patient prognosis, our goal is to find the best indicator to predict the efficacy of neoadjuvant chemotherapy(NAC?in breast cancer patients. A cohort of 808 breast cancer patients treated with NAC and subsequent surgery was analyzed retrospectively. In addition, 2424 people without breast cancer served as the normal group, which included three-fold more individuals compared with the breast cancer group. Receiver operating characteristics (ROC) curves were used to determine the optimal cutoff values of inflammatory markers and compare their predictive capacity. No significant differences in age, PLR, LMR and NMR were noted between the normal group and the patient group. However, the mean value of the NLR was significantly increased in breast cancer patients (2.28) compared with the normal population (2.04) (P < .05). The LMR was significantly associated with age (P = .003), menopausal status (P = .004), cT category (P = .017), cN category (P = .024) and response to NAC (P = .001). The multivariate analysis indicated that among these inflammatory markers, the LMR (6.1 < vs >= 6.1) was the only independent predictive factor for the efficacy of NAC (OR = 1.771, 95% CI = 1.273-2.464, P = .001). A low LMR is considered a favorable predicative factor of the efficacy of NAC in breast cancer patients.

STEAP2 is down-regulated in breast cancer tissue and suppresses PI3K/AKT signaling and breast cancer cell invasion in vitro and in vivo

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (3)

The six-transmembrane epithelial antigen of prostate 2 (STEAP2) protein was identified in advanced prostate cancer, and is highly over-expressed in various types of cancer. This study aimed to investigate the prognostic value and the function of STEAP2 in breast cancer. STEAP2 mRNA and protein expressions in breast normal and cancer tissues, breast cancer cell lines (MCF-7, BT-549, BT-474, MDA-MB-361, HCC1937, and MDA-MB-468) and normal mammary epithelial cell lines (HBL-100 and MCF-10A) were evaluated by immunohistochemistry, real time RT-qPCR and western blotting. The expression of STEAP2 in breast cancer tissues and its value of evaluating the prognosis of breast cancer patients was validated in the Public Databases (Oncomine and Kaplan-Meier plotter database). Lentiviral vectors with STEAP2 cDNA and shRNA were constructed and used to infect breast cancer cell lines and normal mammary epithelial cell line to investigate the effects of STEAP2 up- and down- regulation on the biological behavior of breast cells. The low expression of STEAP2 was detected in breast cancer tissues, which was associated with malignant phenotype and poor prognosis of breast cancer. The public databases analyses were consistent with our findings. STEAP2 up-regulation hindered cellular proliferation, invasion and metastasis abilities by inhibiting EMT process and suppressing PI3K/AKT/mTOR signaling pathway. On the other hand, STEAP2 down-regulation could promote cell proliferation and invasion by inducing EMT and activating the PI3K/AKT/mTOR signaling pathway. Collectively, STEAP2 acted as an anti-oncogene in breast cancer development, which suggested a new research objective for the future studies.

RNA-Seq analysis of peripheral blood mononuclear cells reveals unique transcriptional signatures associated with radiotherapy response of nasopharyngeal carcinoma and prognosis of head and neck cancer

期刊: CANCER BIOLOGY & THERAPY, 0; ()

Radiotherapy is the main treatment for nasopharyngeal carcinoma (NPC); however, radioresistance limits the therapeutic efficacy and prognosis of patients with NPC. Here, we plan to identify the genes involved in radiotherapy response. Peripheral blood mononuclear cells (PBMC) from three paired NPC patients with pre-radiotherapy and post-radiotherapy were extracted. Next-generation deep sequencing was then performed to identify the PBMCs transcripts profiles in response to radiotherapy. Data of gene chip GSE48501 was obtained from Gene Expression Omnibus (GEO) database. The gene integration of differentially expressed genes identified from RNA-Seq data and gene chip was performed using "RobustRankAggreg" package. RNA-Seq data from 44 normal and 519 Head and neck squamous cell carcinoma (HNSCC) tissues (downloaded from TCGA) was integrated into the analysis to further support our study. Cox regression was used to identify risk factors impacting survival. Total of 45 genes were identified to be associated with radiotherapy response. Significantly enriched Gene Ontology (GO) terms and pathways were enriched. Univariate and multivariate analysis suggested the dysregulated genes, CHAC2, CLEC9A, GNG10, JCHAIN, KLRB1, NOG, OLR1, PRELID2, SYT1, VWCE, ZNF443 were associated with survival in HNSCC patients. Our data provide an overview of the profiles of radiotherapy-associated genes, which will facilitate future investigations into the function of radiotherapy resistance.

Durable response to palbociclib and letrozole in ovarian cancer with CDKN2A loss

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (3)

Alterations of the Retinoblastoma (Rb) pathway are frequent in ovarian cancer, typically resulting from CDKN2A down-regulation, CCNE1 amplification, CCND1/2 amplification, and RB1 loss. However, bi-allelic CDKN2A mutation or homozygous deletion is a very rare event, concerning less than 5% of patients. Initial trials with palbociclib in serous ovarian cancer have shown very modest benefit in unselected patient populations, thus underlining the need for a biomarker predicting response. We report the case of a heavily pre-treated patient with a serous ovarian tumor harboring a homozygous deletion of the CDKN2A gene that derived significant, prolonged clinical benefit from palbociclib, a CDK4/6 oral inhibitor, with letrozole. Treatment with palbociclib and letrozole started on February 2018, with an ongoing response after 12 months. In conclusion, homozygous CDKN2A deletion is rare and could be used to predict response to CDK4/6 inhibitors in association with other genomic features. We encourage further trials in this direction.

MiR-421 promotes the development of osteosarcoma by regulating MCPIP1 expression

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (3)

Despite improvements in surgical resection and adjuvant chemotherapy, the prognosis and outcomes of patients with osteosarcoma remains poor due to the occurrence of metastasis or relapse. Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1), a zinc-finger RNA-binding protein, is known to regulate inflammatory responses and repress breast cancer growth. However, the regulation of MCPIP1 by microRNAs has not been clearly elucidated in osteosarcoma. In this study, we found that miR-421 expression was upregulated and MCPIP1 expression was downregulated in the osteosarcoma specimens from patients. Moreover, MCPIP1 expression was inversely correlated with miR-421 expression in the clinical samples. Furthermore, the upregulation of miR-421 and downregulation of MCPIP1 resulted in poor overall survival and severe disease progression, respectively, in the patients with osteosarcoma. Bioinformatics analysis and luciferase reporter gene assays confirmed that miR-421 specifically targets and binds to the 3MODIFIER LETTER PRIME-UTR of MCPIP1. The overexpression of miR-421 induced cell proliferation, invasion, and migration, and the release of pro-inflammatory IL-6 in cultured human osteosarcoma cells. Additionally, the administration of miR-421 to tumor-bearing mice facilitated osteosarcoma growth by downregulating MCPIP1 expression. Taken together, these findings indicate that miR-421 is able to promote the development of osteosarcoma by regulating MCPIP1 expression, and can be a potential therapeutic target for osteosarcoma.

TLK2 enhances aggressive phenotypes of glioblastoma cells through the activation of SRC signaling pathway

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (1)

Glioblastoma are among the most common forms of cancer affecting the central nervous system, and yet there is currently no effective means of treating them. In the current study, we reported that tousled-like kinase 2 (TLK2) is a key factor in glioblastoma that modulates SRC signaling, thereby driving tumor malignancy. TLK2 is commonly upregulated in glioblastoma, and such upregulation was associated with poor patient outcomes. TLK2 overexpression induced cell growth, migration, invasion, and epithelial-mesenchymal transition, and cell cycle arrest, while TLK2 knockdown had the opposite effect. SRC pathway inhibition by Saracatinib resulted in reduced TLK2-mediated glioblastoma migration, invasion, confirming a key role for SRC signaling in regulating the functions of TLK2. Together, our findings demonstrate that glioblastoma TLK2 overexpression acts as a key driver of tumor malignancy via SRC signaling pathway.

IF:2.88

Intestinal microorganisms involved in colorectal cancer complicated with dyslipidosis

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (1)

Background: Abnormal lipid metabolism is considered to be one of main promoters of colorectal cancer (CRC), and intestinal microorganisms may be involved in CRC in patients with abnormal lipid metabolism. Objective: To investigate lipid metabolism in CRC patients and explore the role of intestinal microorganisms in CRC complicated with abnormal lipid metabolism. Methods: Overall, 150 CRC patients in Huzhou Central Hospital from January 2016 to September 2017 were recruited in the present study. Basic patient information and clinical serological indicators were investigated and analyzed. Twenty-one stool samples were collected from patients after receiving informed consent. Next-generation sequencing technology was used to sequence bacterial 16S ribosomal RNA. Bioinformatics analysis was used to profile the microbial composition and screen distinctive bacteria in patients with CRC complicated with abnormal lipid metabolism. Results: Apo B and FFA levels were higher in patients with stage I disease than in patients with other stages. HDL, LDL, Apo B and FFA levels were higher in female patients than in male patients. FFA level was higher in rectal cancer patients than in colon cancer patients. These differences were statistically significant (p < 0.05). The proportion of Escherichia/Shigella was increased in CRC patients with hyperlipoidaemia and hypercholesteremia; the abundance of Streptococcus was increased in CRC patients with hyperlipoidaemia; the abundance of Clostridium XIVa was reduced in CRC patients with hyperlipoidaemia and hypercholesteremia; and the abundance of Ruminococcaceae was reduced in CRC patients with hypercholesteremia. Bilophila and Butyricicoccus were closely related to CRC patients without hyperlipoidaemia or hypercholesteremia, and Selenomonas, Clostridium, Bacteroidetes Slackia, Burkholderiales and Veillonellaceae were closely related to CRC patients with hyperlipoidaemia. Some pathways, including secretion system, chaperones and folding catalysts, amino sugar and nucleotide sugar metabolism, arginine and proline metabolism, glycine, serine and threonine metabolism, histidine metabolism, pores and ion channels, nitrogen metabolism and sporulation, may be involved in lipid metabolism abnormality in CRC patients. Conclusions: Many CRC patients have abnormal lipid metabolism, and the intestinal microbiota is altered in these CRC patients.

IF:2.88

Circular RNA ciRS-7 triggers the migration and invasion of esophageal squamous cell carcinoma via miR-7/KLF4 and NF-kappa B signals

期刊: CANCER BIOLOGY & THERAPY, 2019; 20 (1)

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly cancers worldwide, especially in Eastern Asia. It has been indicated that circular RNAs (circRNA) are the key regulators in the development and progression of human cancers. We therefore evaluated the expression and regulation effects of ciRS-7 on the progression of ESCC, which is a recently identified circRNA and acts as a natural competing endogenous RNA. The expression of ciRS-7 was significantly increased in the ESCC tissues and cells as compared with their corresponding controls. In vitro study showed that ciRS-7 can promote the migration and invasion of ESCC cells. Over expression of miR-7, one of well-known targets of ciRS-7, can attenuate ciRS-7 induced invasion of ESCC cells and over expression of matrix metalloproteinase 2 (MMP2). The expression of stem cell marker Kruppel-like factor-4 (KLF-4), which has been reported as the target of miR7, increased significantly in ciRS-7 transfected ESCC cells. Knockdown of KLF-4 also attenuated over expression of ciRS-7 induced cell invasion. In addition, BAY 11-7082, the inhibitor of NF-kappa B, partially reversed ciRS-7 induced cell invasion. Mechanically studies indicated that ciRS-7 increased the expression of p65 via increasing the phosphorylation of IKK-alpha. Collectively, our present study revealed that ciRS-7 can trigger the migration and invasion of ESCC cells via miR-7/KLF4 and NF-kappa B signals. Targeted inhibition of ciRS-7 might be a potential approach for ESCC treatment.

IF:2.88

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