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Clinical characteristics and prognostic analysis of multiple primary malignant neoplasms in patients with lung cancer

期刊: CANCER GENE THERAPY, 2019; 26 (11-12)

Retrospective analysis of data from 14,528 lung cancer patients with multiple primary malignant neoplasm (MPMN) revealed that 2.5% (364/14,528) were MPMN cases and 96.2% (350/364) were diagnosed with two primary malignancies, 3.6% (13/364) with three primary malignancies, and 0.3% (1/364) with four primary malignancies. Among 350 lung cancer patients diagnosed with two primary malignancies, 26.6% (93/350) had lung cancer diagnosed first (LCF) and 73.4% (257/350) had other cancers diagnosed initially (OCF), whereas synchronous MPMN (SMPMN) accounted for 21.1% (74/350) and metachronous MPMN (MMPMN) accounted for 78.9% (276/350) of the cases. Detection of first primary neoplasms were at an early stage for LCF patients and the age of the first lung cancer diagnosis was 59.3 years vs. 55.4 years in the OCF group (P = 0.008), whereas the onset age of second primary neoplasm diagnosis was similar in both groups (62.5 and 61.6 years, P = 0.544). Median survival times of MMPMN and SMPMN patients in the LCF group were 6.83 and 2.42 years and in the OCF group 8.67 years and 2.25 years, respectively. Multivariate analysis showed that SMPMN, LCF and the age of the primary cancer diagnosed first (>= 60 years) and NSCL staging > II were significant independent factors for inferior prognosis of patients.

JIF:4.68

c-Myc induced upregulation of long non-coding RNA SNHG16 enhances progression and carcinogenesis in oral squamous cell carcinoma

期刊: CANCER GENE THERAPY, 2019; 26 (11-12)

Small nucleolar RNA host gene 16 (SNHG16) has been documented to be involved in the pathogenesis of human cancers. Here, we elucidated the biological roles and regulatory mechanism of SNHG16 in the pathogenesis of oral squamous cell carcinoma (OSCC). In this paper, we found that c-Myc and SNHG16 were overexpressed in OSCC tissues and cell lines compared with normal tissues and normal human oral keratinocytes cells. There was a notable positive correlation between SNHG16 and c-Myc expression in OSCC tissues. c-Myc silencing by either shRNA c-Myc or by 10058-F4 (c-Myc inhibitor) resulted in a dose-dependent reduction in SNHG16 levels in CAL-27 and TSCCA cells; conversely, upregulation of c-Myc by pcDNA c-Myc markedly increased SNHG16 expression. Depletion of SNHG16 in CAL-27 cells strikingly inhibited cell proliferation, migration and invasion, as indicated by downregulation of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2 and MMP-9. Moreover, depletion of SNHG16 induced cell apoptosis and inhibited epithelial-to-mesenchymal transition as indicated by induction of cleaved caspase-3 and epithelial cadherin (E-cadherin) along with reduction of N-cadherin and Snail. Intriguingly, c-Myc knockdown led to the similar functional effects as that of SNHG16 knockdown in TSCCA cells. However, these changes caused by c-Myc knockdown were abrogated by SNHG16 overexpression. Knockdown of SNHG16 conspicuously repressed tumor growth in nude mice. Similarly, silencing of c-Myc markedly inhibited tumor growth and reduced SNHG16 expression in nude mice. Moreover, overexpression of SNHG16 blocked the inhibitory effect of c-Myc silencing on tumor growth in vivo. Thus, we conclude that c-Myc-induced upregulation of SNHG16 enhances progression and carcinogenesis in OSCC.

JIF:4.68

Down-regulated long non-coding RNA RNAZFHX4-AS1 suppresses invasion and migration of breast cancer cells via FAT4-dependent Hippo signaling pathway

期刊: CANCER GENE THERAPY, 2019; 26 (11-12)

Breast cancer is ranked as the second leading cause of cancer-related deaths among women. Accumulating evidences have revealed that long non-coding RNAs (lncRNAs) are involved in human tumorigenesis owing to the regulation of essential pathways for tumor initiation and progression. Herein, the current study aimed to explore the regulatory mechanism of lncRNA ZFHX4-AS1 in breast cancer in relation to the Hippo signaling pathway. Initially, microarray analysis was conducted to screen out differentially expressed lncRNAs related to breast cancer. Next, the functional role of lncRNA ZFHX4-AS1 in breast cancer was determined using ectopic expression, knockdown, and reporter assay experiments. Subsequently, lncRNA ZFHX4-AS1, TAF4, TAZ, and YAP expressions were determined, followed by verification of the targeting relationship between lncRNA ZFHX4-AS1 and TAF4. Then cell proliferation, invasion, migration, cell cycle, and apoptosis were measured. Lastly, tumor growth and metastasis were detected by tumor xenograft in nude mice. LncRNA ZFHX4-AS1 was found to be highly expressed while FAT4 was poorly expressed in breast cancer tissues. FAT4 was the target gene of lncRNA ZFHX4-AS1, and lncRNA ZFHX4-AS1 silencing increased FAT4 expressions, while decreased YAP and TAZ expressions. In addition, knockdown of lncRNA ZFHX4-AS1 suppressed breast cancer cell proliferation, migration, and invasion as well as tumor growth, blocked cell cycle entry, while promoted cell apoptosis by inhibiting the Hippo signaling pathway. In conclusion, our findings reveal that lncRNA ZFHX4-AS1 silencing exerts an inhibitory effect on breast cancer development by suppressing the activation of the Hippo signaling pathway via FAT4.

JIF:4.68

Upregulating microRNA-498 inhibits gastric cancer proliferation invasion and chemoresistance through inverse interaction of Bmi1

期刊: CANCER GENE THERAPY, 2019; 26 (11-12)

This study aimed to analyze the functions of microRNA 498 (miR-498) on gastric cancer (GC) cell proliferation migration and cisplatin chemosensitivity. QTR-PCR found that miR-498 was markedly downregulated in GC cell lines and human GC tumors. It was discover that, lentivirus-mediated miR-498 overexpression inhibited cancer cell proliferations in vitro and in vivo, invasion and cisplatin chemoresistance. Bmi1 was demonstrated to be directly regulated by miR-498 in GC cell lines. Moreover, Bmi1 upregulation was found to reverse the tumor-suppressing functions of miR-498 in GC. Therefore, this study presented evidence showing miR-498 expression decreased in GC, and overexpressing miR-498 had significant inhibitory effects on GC development, likely through the inverse interaction of Bmi1.

JIF:4.68

Transferrin receptor-involved HIF-1 signaling pathway in cervical cancer

期刊: CANCER GENE THERAPY, 2019; 26 (11-12)

Cervical cancer is one of the most prevalent gynecologic malignancies and has remained an intractable cancer over the past decades. We analyzed the aberrant expression patterns of cervical cancer using RNA-Seq data from The Cancer Genome Atlas (TCGA). A total of 3352 differently expressed genes (DEGs) were identified in 306 cervical cancer samples compared with 3 control samples, with 1401 genes upregulated and 1951 downregulated. Under Kaplan-Meier analysis, 76 out of these DEGs with a significantly different survival rate between patients with high and low expression groups were picked out and uploaded to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, which identified a transferrin receptor (TFRC)-involved HIF-1 signaling pathway (p < 0.05). Clinical data analysis showed that high TFRC expression in cervical cancers was associated with incrementally advanced stage, tumor status, and lymph nodes (all p-values <0.05), while multivariate analysis revealed that TFRC remained an independent prognostic variable for poor overall survival. In conclusion, our data indicated that the TFRC-involved HIF-1 signaling pathway may play a crucial role in cervical cancer.

JIF:4.68

High expression of UBE2T predicts poor prognosis and survival in multiple myeloma

期刊: CANCER GENE THERAPY, 2019; 26 (11-12)

Multiple myeloma (MM) is one of hematological malignancies, characterized by malignant proliferation of plasma cells. Biomarkers play an important role in evaluating the development and prognosis of MM. Ubiquitin- conjugating enzyme E2T (UBE2T) is served to connect with particular E3 ubiquitin ligase to degraded-related substrates, contributing to DNA repair in the Fanconi anemia pathway. Also, numerous evidences reported that UBE2T is closely related to cell proliferation and carcinogenesis. However, the relationship between MM and UBE2T has not been studied. Here, we integrated eight datasets and analyzed the relationship of expression of UBE2T and ISS, 1q21, relapse and survival in MM 2684 patients (totally 2893 samples). We found that the expression of UBE2T increased with the deterioration of MM (P = 1.4e-07), especially in the early stage. UBE2T is closely related to IgG serotype MM (P = 6.9e-05). High expression of UBE2T is associated with poor survival and prognosis (EFS: P = 1.43e-03, OS: P = 5.47e-05). UBE2T is likely to play a part in the cell division pathway, affecting the survival and prognosis of MM. Therefore, UBE2T could be considered as an early alternative biomarker for the prognosis of MM.

JIF:4.68

Enhanced expressions of FHL2 and iASPP predict poor prognosis in acute myeloid leukemia

期刊: CANCER GENE THERAPY, 2019; 26 (1-2)

iASPP is a negative regulator of the apoptotic function of p53, and it can enhance the ability of hematopoietic stem cells to self-renew and resist chemo- and radiation therapy. Recent study showed that iASPP could impact the proliferation and apoptosis of leukemia cells by interacting with FHL2. However, whether they have prognostic significance in acute myeloid leukemia (AML) is unknown. Eighty-four AML patients with FHL2 and iASPP expression data from The Cancer Genome Atlas database were enrolled in the study. Patients with high expressions of FHL2 and iASPP had significantly shorter event-free survival (EFS) and overall survival (OS) than patients with low expressions (P = 0.005, P = 0.003, respectively). Univariate analysis indicated that high expressions of FHL2 or iASPP were unfavorable for EFS and OS (all P < 0.05), while multivariate analysis confirmed that high FHL2 expression was an independent risk factor for EFS and OS (all P < 0.05). In patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, EFS and OS were not significantly different between FHL2 or iASPP high- and low-expression groups. Our results suggested that high expressions of FHL2 and iASPP were poor prognostic factors for AML, but the prognostic effect might be overcome by allo-HSCT.

JIF:4.68

miR-182 regulates trastuzumab resistance by targeting MET in breast cancer cells

期刊: CANCER GENE THERAPY, 2019; 26 (1-2)

It has been found that microRNAs (miRNAs) play a key role in drug resistance. The purpose of the current study was to investigate the function of miR-182 in trastuzumab resistance in breast cancer cells. The results showed that both breast cancer SKBR3 trastuzumab-resistant cells (SKBR3/TR) and BT474 trastuzumab-resistant cells (BT474/TR) were associated with miR-182 downregulation compared with their parental cells. Ectopic expression of the miR-182 mimic inhibited trastuzumab resistance, decreasing the invasion and migration of these trastuzumab-resistant cells. However, the miR-182 inhibitor increased trastuzumab resistance, cell invasion, and migration in the parental cells. In addition, MET is a directly targeted gene of miR-182 in breast cancer cells. MET knockdown showed an inhibitory effect of trastuzumab resistance on trastuzumab-resistant cells. In contrast, MET overexpression in SKBR3 cells produced an effect that promotes resistance to trastuzumab. Moreover, we revealed that overexpression of miR-182 reduced trastuzumab resistance in trastuzumab-resistant cells due in part to MET/PI3K/AKT/mTOR signaling pathway inactivation. Furthermore, miR-182 could also sensitize SKBR3/TR cells to trastuzumab in vivo. In conclusion, our results suggest that the activation of miR-182 or inactivation of its target gene pathway could be used as a new method to reverse trastuzumab resistance in breast cancer.

JIF:4.68

The effect of gene therapy on postoperative recurrence of small hepatocellular carcinoma (less than 5cm)

期刊: CANCER GENE THERAPY, 2019; 26 (3-4)

To observe the curative effect of surgery combined with gene therapy on small hepatocellular carcinoma. Seventy-seven patients with small hepatocellular carcinoma (diameter < 5 cm) underwent surgical resection. The tumor located at the edge of the liver was treated by local excision or irregular hepatectomy. The tumor in the center of the liver was resected by hepatic lobectomy in order to ensure at least a 2-cm safety margin. Fifty-four patients underwent gene therapy (gene group) one or two times before operation, whereas 23 patients underwent surgery alone (control group) selected by themselves. The injectable gene was made of ADV-TK (adenovirus containing thymidine kinase suicide gene, with a concentration of 5 x 10(12)/ml). The prognosis of patients was analyzed by imaging twice a year. In the gene group, the 1-, 3-, and 5-year survival rates were 91.4, 63.6, and 52.1%. In the control group, the survival rates were 84.3, 54.4, and 32.6%, respectively. There was a significant difference in the overall survival rates between two groups. Factors associated with overall survival in univariate analysis included bilirubin, prothrombin activity, cirrhosis, and gene therapy (P < 0.05). In the multivariate analysis, it included cirrhosis, gene therapy, and bilirubin. The gene therapy hepatocellular carcinoma patients with a diameter < 5 cm could significantly reduce recurrence after operation. It was worthy of being popularized.

JIF:4.68

GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2

期刊: CANCER GENE THERAPY, 2019; 26 (3-4)

To explore the mechanisms of GINS2 on cell proliferation and apoptosis in thyroid cancer (TC) cells. Expressions of GINS2 were inhibited in K1 and SW579 cells using gene interference technology. The abilities of proliferation and apoptosis, and cell cycle were determined by MTT assay and flow cytometric assay. The downstream molecules of GINS2 were searched by microarray and bioinformatics and validated by qRT-PCR and western blotting. In the in vivo study, the tumor growth was compared and the whole-body fluorescent imaging was analyzed. After GINS2 was interfered, cell proliferation was significantly inhibited (P < 0.01) and apoptosis rate increased (P < 0.01) in both K1 and SW579 cells. Cell cycle changed significantly in K1 cells, but not in SW579 cells. With bioinformatics upstream analysis, TGF-beta 1 was found as the most significantly upstream regulator. Expressions of TGF-beta 1 and its downstream target molecules CITED2 and LOXL2 were validated and found downregulated significantly in mRNA and protein levels (P < 0.05). The results of the nude mouse xenograft assay suggested that the volume and weight of tumor in ones infected with shGINS2 were statistically smaller than controls (P < 0.05). GINS2 plays an important role in cell proliferation and apoptosis of thyroid cancer by regulating the expressions of CITED2 and LOXL2, which may be a potential biomarker for diagnosis or prognosis and a drug target for therapy.

JIF:4.68

Adenoviral delivery of VHL suppresses bone sarcoma cell growth through inhibition of Wnt/beta-catenin signaling

期刊: CANCER GENE THERAPY, 2019; 26 (3-4)

The VHL tumor suppressor gene is frequently inactivated in several human tumors, including bone sarcomas. We previously identified that reduced expression of VHL protein is implicated in sarcomagenesis. However, the underlying biological functions of restored VHL protein expression have not been clearly elucidated in bone sarcomas. Here we initially constructed a recombinant adenovirus 5-VHL vector (Ad5-VHL) and evaluated its expression in bone sarcomas, and antitumor activity in vitro and in vivo. We found that the adenovirus-mediated increase of VHL significantly suppresses bone sarcoma cell growth, attributed to induction of apoptosis mediated by increased caspase-3 activity and modulated Bcl-2 protein family. This suppression effect involves inhibition of Wnt/beta-catenin signaling and upregulation of GSK-3 beta. Moreover, Ad5-VHL showed a dramatic antitumor effect on a chondrosarcoma xenograft model. These findings establish that Ad5-VHL suppresses bone sarcoma cell growth by inhibiting Wnt/beta-catenin signaling, and may be a novel target for gene-based therapy of bone sarcomas.

JIF:4.68

miR-140-5p inhibits the proliferation and enhances the efficacy of doxorubicin to breast cancer stem cells by targeting Wnt1

期刊: CANCER GENE THERAPY, 2019; 26 (3-4)

MicroRNAs (miRNAs) are a group of small non-coding single-stranded RNAs molecules, the dysregulation of which plays a critical role in the initiation and biological progression of malignancies. The current study demonstrated that miR-140-5p was frequently downregulated in breast cancer stem cells (BCSCs), and miR-140-5p mimics could inhibit the proliferation of BCSCs. Moreover, Wnt1 was a direct target of miR-140-5p, as was proved by luciferase reporter assays. miR-140-5p mimics could downregulate the wnt1 mRNA and protein levels in MCF-7 and MDA-MB-231 cells. Furthermore, miR-140 mimics could enhance the sensitivity of BCSCs to doxorubicin (Dox) through the Wnt1/ABCB1 pathway both in vitro and vivo. Our findings have presented a novel miRNA-mediated regulatory network for BCSCs, which may provide a potential therapeutic target for breast cancer.

JIF:4.68

Increased invasive phenotype of CSF-1R expression in glioma cells via the ERK1/2 signaling pathway

期刊: CANCER GENE THERAPY, 2019; 26 (5-6)

Glioma is a common malignant tumor of the central nervous system (CNS) that has no effective treatment. In this study, we report that colony-stimulating factor-1 receptor (CSF-1R) is a key mediator of malignant features in glioma via modulation of the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. In general, CSF-1R upregulation in glioma is associated with poor histologic grade and sursvival. Enforced expression of CSF-1R is sufficient to enhance cell growth, migration, invasion, and epithelial-mesenchymal transition, while CSF-1R silencing suppresses the above-described malignant phenotypes. Mechanistic investigations show that CSF-1R promotes activation of the ERK1/2 signaling pathway. Inhibition of the ERK1/2 pathway by SCH772984 reduces CSF-1R-induced migration, invasion, and lung metastasis of glioma cells, thus establishing a role of the ERK1/2 signaling pathway in mediating the CSF-1R effect. In summary, our results suggest that CSF-1R overexpression in gliomas contributes to the malignant behaviors of cancer cells.

JIF:4.68

High expression levels of SMAD3 and SMAD7 at diagnosis predict poor prognosis in acute myeloid leukemia patients undergoing chemotherapy

期刊: CANCER GENE THERAPY, 2019; 26 (5-6)

The SMAD family (SMAD1-9) was critically important for regulating cellular process through transforming growth factor-beta signaling pathway, and contributed to carcinogenesis; however, their prognostic roles in acute myeloid leukemia (AML) remained unclear. This study collected 84 de novo AML patients treated with chemotherapy and 71 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Kaplan-Meier survival estimate indicated that among SMAD1-9, high SMAD3 and SMAD7 expression were both associated with poor event-free survival (EFS) and overall survival (OS; all P < 0.05) in AML patients undergoing chemotherapy; and high SMAD6 expression was associated with shorter EFS and OS (all P < 0.01) in patients underwent allo-HSCT. Multivariate analysis showed that only high SMAD7 expression had adverse effect on EFS and OS (P = 0.021, 0.026) independently. Furthermore, High SMAD3 and SMAD7 expressers had significantly shorter EFS and OS than low expressers (P = 0.006, 0.001). In AML patients who went through allo-HSCT, there were no significant differences for EFS and OS between patients with high and low-expression SMAD3 or SMAD7. Our study suggested that high expression of SMAD3 and SMAD7 predicted adverse prognosis in AML patients undergoing chemotherapy and SMAD7 was a better prognostic marker than SMAD3. Their prognosis impact may be overcome by allo-HSCT.

JIF:4.68

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