Δευτέρα, 25 Μαρτίου 2019

American Journal of Cancer Research


Select item 30906644
1.
Am J Cancer Res. 2019 Feb 1;9(2):458. eCollection 2019.
CSF-1R regulates non-small cell lung cancer cells dissemination through Wnt3a signaling [Retraction].
[No authors listed]
Abstract
[This retracts the article on p. 2144 in vol. 7, PMID: 29218239.].

Retraction of
CSF-1R regulates non-small cell lung cancer cells dissemination through Wnt3a signaling. [Am J Cancer Res. 2017]
PMID: 30906644
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Select item 30906643
2.
Am J Cancer Res. 2019 Feb 1;9(2):455-457. eCollection 2019.
Erratum: Alpinumisoflavone suppresses tumour growth and metastasis of clear-cell renal cell carcinoma.
Wang T1, Jiang Y2, Chu L2, Wu T3, You J1.
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Abstract
[This corrects the article on p. 999 in vol. 7, PMID: 28469971.].

Erratum for
Alpinumisoflavone suppresses tumour growth and metastasis of clear-cell renal cell carcinoma. [Am J Cancer Res. 2017]
PMID: 30906643
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3.
Am J Cancer Res. 2019 Feb 1;9(2):449-454. eCollection 2019.
SHEDding light on the role of Pragmin pseudo-kinases in cancer.
Roche S1, Lecointre C1, Simon V1, Labesse G2.
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Abstract
The human kinome comprises more than 50 pseudo-kinases with unclear biological function due to the absence of apparent catalytic activity, and therefore, with presumably little interest for cancer drug discovery. However, it is now acknowledged that several of them, such as Pragmin family members, play roles as important as those of active kinases in human cancer. How these pseudo-kinases promote tumor formation is largely unknown. Recently, independent structural analyses of three Pragmin pseudo-kinases (Pragmin, SGK223, and SGK269/PEAK1) revealed a split helical dimerization (SHED)-based mechanism of action. Additional sequence-structure analysis identified C19orf35 as a new member of the Pragmin family. Based on the results of these molecular studies, we present a unified model on how Pragmin pseudo-kinases may regulate oncogenic signaling, and suggest potential therapeutic strategies to block their tumor activity.

KEYWORDS:
Pseudo-kinase; cancer; cell growth; cell migration; cell signaling; phosphorylation; structure; therapeutic target

PMID: 30906642
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4.
Am J Cancer Res. 2019 Feb 1;9(2):434-448. eCollection 2019.
Combining peptide TNIIIA2 with all-trans retinoic acid accelerates N-Myc protein degradation and neuronal differentiation in MYCN-amplified neuroblastoma cells.
Otsuka K1, Sasada M1,2,3, Iyoda T4, Nohara Y1, Sakai S1, Asayama T1, Suenaga Y3, Yokoi S3, Higami Y2,5, Kodama H6, Fukai F1,2.
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Abstract
Neuroblastoma is one of the common solid tumors of childhood. Nearly half of neuroblastoma patients are classified into the high-risk group, and their 5-year event-free survival (EFS) rates remain unsatisfactory in the range of 30-40%. High-risk neuroblastoma is characterized by amplification of the MYCN gene and excessive expression of its protein product, N-Myc. Because N-Myc is a transcription factor for various pro-proliferative proteins, the excessive expression causes aberrant or blocked neuronal differentiation during development of sympathetic nervous system, which is a central aspect of neuroblastoma genesis. The current main treatment for high-risk neuroblastoma is intensive chemotherapy using anti-cancer drugs that induce apoptosis in tumor cells, but intensive chemotherapy has another serious risk of long-lasting side effects, so-called "late effects", that occur many years after chemotherapy has ended. As a solution for such situation, differentiation therapy has been expected as a mild chemotherapy with a low risk of late effects, and an application of retinoic acid (RA) and its derivatives as treatment for high-risk neuroblastoma has long been attempted. However, the clinical outcome has not been sufficient with the use of retinoids, including all-trans retinoic acid (ATRA), mainly because of the inhibition of differentiation caused by N-Myc. In the present study, we succeeded in synergistically accelerating the ATRA-induced neuronal differentiation of MYCN-amplified neuroblastoma cells by combining a peptide derived from tenascin-C, termed TNIIIA2, which has a potent ability to activate β1-integrins. Accelerated differentiation was caused by a decrease in N-Myc protein level in neuroblastoma cells after the combined treatment of TNIIIA2 with ATRA. That is, combination treatment using ATRA with TNIIIA2 induced proteasomal degradation in the N-Myc oncoprotein of neuroblastoma cells with MYCN gene amplification, and this caused acceleration of neuronal differentiation and attenuation of malignant properties. Furthermore, an in vivo experiment using a xenograft mouse model showed a therapeutic potential of the combination administration of ATRA and TNIIIA2 for high-risk neuroblastoma. These results provide a new insight into differentiation therapy for high-risk neuroblastoma based on N-Myc protein degradation.

KEYWORDS:
ATRA; N-Myc; Neuroblastoma; differentiation therapy; integrin; mycn; proto-oncogene; retinoic acid; tenascin-C; ubiquitin-proteasome system

PMID: 30906641
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Select item 30906640
5.
Am J Cancer Res. 2019 Feb 1;9(2):429-433. eCollection 2019.
A sex-dimorphic mouse model of esophageal squamous cell carcinoma.
Zheng D1, Li Z1.
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Abstract
Sexual dimorphism in the incidence of human esophageal cancer, including both esophageal adenocarcinoma and squamous cell carcinoma, shows male dominancy. However, the mechanisms that underlie sexual dimorphism of esophageal cancer have been understudied in vivo due to the lack of sex-dimorphic mouse models. Here, we developed a sex-dimorphic mouse model of esophageal squamous cell carcinoma (ESCC) using a lower amount of 4-nitroquinoline-1-oxide (4-NQO) and a shorter latency of tumorigenesis compared to the traditional carcinogenesis procedures. In this model, we found that male mice were highly sensitive to the tumorigenesis of ESCC whereas female mice were resistant to it. This model provided us an opportunity for investigating the mechanisms underlying sexual dimorphism of ESCC in vivo and for better understanding the sex-dimorphic incidence of ESCC in humans.

KEYWORDS:
Sexual dimorphism; esophageal squamous cell carcinoma; mouse model

PMID: 30906640
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Select item 30906639
6.
Am J Cancer Res. 2019 Feb 1;9(2):424-428. eCollection 2019.
Genetic ablation of mammary ducts through foxa1 prevents breast cancer occurrence.
Zheng D1, McLaughlin SA2, Kaestner KH3, Li Z1.
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Abstract
Risk reducing mastectomy is the only surgical approach for the prevention of breast cancer in women with deleterious genetic mutations or in those deemed to be at extremely high risk. However, up to 10.5% of these women still developed breast cancer. Thus, developing new strategies for complete prevention of breast cancer is imperative. Mammary ducts were ablated by mammary-specific ablation of forkhead box protein A1 (Foxa1). Mammary tumorigenesis was induced in control and mammary-specific Foxa1 knockout mice using carcinogens. No mammary tumors were observed in these knockout mice compared to four types of breast tumors induced in control mice. We present a promising novel strategy for the prevention of breast cancer by genetic ablation of mammary ducts via targeting Foxa1.

KEYWORDS:
Foxa1; breast cancer prevention; carcinogenesis; mammary ducts; mastectomy

PMID: 30906639
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Select item 30906638
7.
Am J Cancer Res. 2019 Feb 1;9(2):415-423. eCollection 2019.
ADP-ribosylation factor-like 4C is a predictive biomarker of poor prognosis in patients with renal cell carcinoma.
Isono T1, Chano T2, Yoshida T3, Makino A1, Ishida S1, Suzaki M1, Kageyama S3, Kawauchi A3, Yonese J4, Yuasa T4.
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Abstract
Renal cell carcinoma (RCC) has the high mortality rate among urological malignancies. The development of RCC cannot be effectively reduced by molecular targeted therapies based on nutrient deprivation, such as inhibition of tumor angiogenesis. The objective of this study was to identify predictive biomarkers of poor prognosis and therapeutic molecular targets in patients with RCC. Two independent cohorts were analyzed in the present study. Global transcriptomics were used in the first cohort (43 patients with RCC) to identify biomarker genes. Each identified biomarker was subsequently analyzed using immunohistochemistry in the second cohort (97 patients with RCC). Following transcriptomics, biomarkers were evaluated using receiver operating characteristic curve analysis. Predictive accuracy for poor survivals was assessed using the log-rank test and Cox multivariate analysis. Global transcriptomic analysis in the first cohort focusing on cases with survival periods <2 years after initial diagnosis of metastasis detected seven overexpressed genes, which correlated with poor prognosis. The ADP-ribosylation factor-like 4C (ARL4C) exhibited the best accuracy in the receiver operating characteristic curve analysis and predicted poor survival in the first cohort (log-rank test, P<0.001; Cox multivariate analysis, hazard ratio =167, P=0.005). In the second cohort, the expression of ARL4C was semi-quantitatively evaluated through immunohistochemistry. Twenty-seven cases showed high levels of ARL4C, confirming a significant association with shorter survivals (log-rank test, P<0.001; Cox multivariate analysis, hazard ratio =9.41, P=0.004). ARL4C was shown to be a predictive biomarker for poor prognosis in patients with RCC and may be a novel target in the treatment of RCC.

KEYWORDS:
ADP-ribosylation factor-like 4C (ARL4C); global transcriptome; immunohistochemistry; metastasis; next generation sequencer (NGS); poor prognosis; predictive accuracy; predictive biomarkers; primary tissues; renal cell carcinoma (RCC)

PMID: 30906638
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Select item 30906637
8.
Am J Cancer Res. 2019 Feb 1;9(2):406-414. eCollection 2019.
Clinical benefits of Livin peptide-loaded DCs/CIKs combined with chemotherapy in advanced non-small cell lung cancer.
Zhang L1, Xu Z1, Chen X2, Duan Y1, Chen Z1, Sun J1.
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Abstract
Previous studies showed that Livin, a member of inhibitors of apoptosis protein (IAP), played an important role in drug and radiation resistance. When the expression of Livin was blocked, the sensitivity to both chemotherapy and radiotherapy was improved in lung cancer cells. A total of 79 patients diagnosed with non-small cell lung cancer (NSCLC) were enrolled into the current study from Jan 2012 to Apr 2016. The Livin and MUC-1 groups received one-cycle autologous DCs/CIKs infusion on days 11 to 14 additionally. The clinical efficacy, immune index, KPS score and adverse events were compared among the three groups. Median progression-free survival (mPFS) in Livin and MUC-1 groups was significantly longer than that in Chemo group (195 and 211 vs 138 days, P < 0.05), and the objective response rate (ORR) in Livin and MUC-1 groups was significantly higher than that in Chemo group (23.1% and 22.2% vs 5.1%, P < 0.05). The Tetramer value after treatment in Livin group was significantly higher than that before treatment (4.07 ± 3.77 vs 3.16 ± 3.82, P < 0.05). The concentration of Livin antibody in patients' peripheral blood before and after treatment in Livin group had no significant difference (P > 0.05). As for KPS score, scarce decrease was found in Livin and MUC-1 groups after chemotherapy treatment (0.77 ± 6.41 and 0.37 ± 5.18, respectively). However, obvious decrease of KPS score (P < 0.039) was recorded in Chemo group (3.85 ± 6.33). There was no significant difference in disease control rate (DCR), overall survival (OS), T cell subsets, cytokine levels (IFN-γ and IL-2) and adverse events between the three groups (P > 0.05). Livin peptide could be a novel substitute to trigger cell immunity by loading DCs in combination with chemotherapy in NSCLC.

KEYWORDS:
Dendritic cells; Livin peptide; cytokine-induced killer cells; cytotherapy; non-small-cell lung cancer

PMID: 30906637
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Select item 30906636
9.
Am J Cancer Res. 2019 Feb 1;9(2):390-405. eCollection 2019.
Inhibition of invasive pancreatic cancer: restoring cell apoptosis by activating mitochondrial p53.
Cheng J1, Okolotowicz KJ1, Ryan D1, Mose E2, Lowy AM2, Cashman JR1.
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Abstract
Pancreatic ductal adenocarcinoma (PDAC), constitutes >90% of pancreatic cancers (PC) and is one of the most aggressive human tumors. Standard chemotherapies for PDAC (e.g., gemcitabine, FOLFIRINOX, etc.) has proven to be largely ineffective. Herein, we report a novel molecule (i.e., compound 1) that potently inhibits proliferation and induces apoptosis of PDAC cells. As we observed in other cancer types (i.e., colorectal, breast cancer), the effect of 1 against PDAC cells is also related to microtubule destabilization and DNA damage checkpoint activation. However, in PDAC cells, the inhibitory effect of 1 was mainly controlled by mitochondrial p53-dependent apoptosis. Compound 1 worked with cells of different p53 mutant status and affected p53 activation/phosphorylation not simply by stabilizing p53 protein but through antagonizing anti-apoptotic effects of Bcl-xL and restoring p53 to activate mitochondrial-apoptotic pathways (i.e., cytochrome c release, caspase activation and PARP cleavage). Compound 1 was more efficient than a typical PDAC combination therapy (i.e., gemcitabine with paclitaxel) and showed synergism in inhibiting PDAC cell proliferation with gemcitabine (or gemcitabine with paclitaxel). This synergism varied between different types of PDAC cells and was partially controlled by the phosphorylation of p53 on Serine15 (phospho-Ser15-p53). In vivo studies in an orthotopic syngeneic murine model showed that 1 (20 mg/kg/day, 28 days, i.p.) inhibited tumor growth by 65% compared to vehicle-treated mice. No apparent acute or chronic toxicity was observed. Thus, compound 1 utilizes a distinct mechanism of action to inhibit PC growth in vitro and in vivo and is a novel anti-PDAC compound.

KEYWORDS:
DNA damage pathway; Pancreatic cancer; mitochondrial control of apoptosis; orthotopic syngeneic model; p53 activation; pancreatic ductal adenocarcinoma (PDAC)

PMID: 30906636
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Select item 30906635
10.
Am J Cancer Res. 2019 Feb 1;9(2):378-389. eCollection 2019.
Epithelial ovarian cancer: feasibility of image-guided intratumoral radiofrequency hyperthermia-enhanced direct gene therapy.
Jin G1,2, Li Y1,3, Zhang F1, Li P1, Zhao L1, Zhou Y1, Ji H1,4, Pietrini S1, Zhai B2, Yang X1.
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Abstract
The aim of this study was to develop an interventional oncologic technique, "Image-guided intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus-thymidine kinase (HSV-TK) gene therapy of ovarian cancer. This study consisted of three portions: (1) serial in-vitro experiments to establish "proof-of-principle" of this novel technique using human ovarian cancer cells; (2) serial in-vivo experiments to validate technical feasibility using animal models with the same orthotopic ovarian cancers; and (3) serial investigations into the underlying bio-molecular mechanisms of this technique. We included four subject groups: (i) combination therapy with RFH+HSV-TK gene therapy; (ii) gene therapy-only; (iii) RFH-only; and (iv) Phosphate-buffered saline (PBS). For in-vitro experiments, confocal microscopy and MTS assays were performed to quantify HSV-TK gene expression and assess cell viability. For in-vivo experiments, bioluminescence optical and ultrasound imaging were used to assess therapeutic effectiveness. These results were correlated with subsequent pathologic/laboratory studies to further elucidate the biologic mechanisms of this technique. In in-vitro experiments, combination therapy resulted in the lowest cell proliferation and greatest increase in HSV-TK gene expression among four subject groups. In in-vivo experiments, combination therapy lead to significant decreases of bioluminescence signals and sizes of tumors in combination therapy by optical and ultrasound imaging. Pathology/laboratory examinations confirmed the significantly increased expression of Bax, Caspase-3, HSP70, IL-2, and CD94 in cancer tissues subjected to combination therapy. "Image-guided intratumoral RFH-enhanced direct gene therapy" is an effective interventional oncologic technique which functions through apoptotic/anti-tumor immunity pathways. This technical development may open new avenues for treating ovarian cancer.

KEYWORDS:
HSV-TK/GCV; Radiofrequency hyperthermia; gene therapy; molecular image; ovarian cancer

PMID: 30906635
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Select item 30906634
11.
Am J Cancer Res. 2019 Feb 1;9(2):363-377. eCollection 2019.
SFRP4 is a prognostic marker and correlated with Treg cell infiltration in pancreatic ductal adenocarcinoma.
Yang MW1, Tao LY1, Yang JY1, Jiang YS1, Fu XL1, Liu W1, Huo YM1, Li J1, Zhang JF1, Hua R1, Qin XR1, Sun YW1, Liu DJ1.
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Abstract
Secreted Frizzled-Related Protein 4 (SFRP4), a member of secreted frizzled-related protein family, has been found as a vital modulator in cell proliferation, cell self-renew and apoptosis through Wnt signaling transduction pathway. In the present study, we re-analyzed the expression pattern of SFRPs in Gene Expression Omnibus (GEO) datasets and evaluated the expression of SFRP4 at protein level in both KrasG12D/+; Trp53R172H/+; Pdx1-Cre; (KPC) mice and human pancreatic ductal adenocarcinoma (PDAC) tissue. We found that the expression of SFRP4 increased gradually in PanINs and PDAC lesions in KPC mice and high expression of SFRP4 was much more common in tumor lesions compared to the adjacent non-tumor tissues. Then we performed Kaplan-Meier survival and Cox regression analysis and found that high expression of SFRP4 in the serum and tumor lesions predicted poor prognosis for pancreatic cancer patients. Furthermore, we demonstrated that SFRP4 positively correlated with FOXP3+ Treg cells infiltration while the down-regulation of SFRP4 in tumor cells impaired the production of cytokines and the recruitments of T cells. This study suggested that SFRP4 can be a novel prognostic biomarker and potential therapeutic target for pancreatic cancer.

KEYWORDS:
SFRP4; biomarkers; pancreatic ductal adenocarcinoma; prognosis; regulatory T-cell

PMID: 30906634
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Select item 30906633
12.
Am J Cancer Res. 2019 Feb 1;9(2):347-362. eCollection 2019.
DSE regulates the malignant characters of hepatocellular carcinoma cells by modulating CCL5/CCR1 axis.
Liao WC1,2, Yen HR3,4,5, Liao CK1,2, Tseng TJ1,2, Lan CT1,2, Liu CH1,2.
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Abstract
Abnormal expression of dermatan sulfate epimerase (DSE) has been found in many types of cancer, while its expression and biological functions in hepatocellular carcinoma (HCC) progression remains obscure. Here we report that DSE, the enzyme that catalyzes the conversion of chondroitin sulfate (CS) to dermatan sulfate (DS), is a critical mediator of malignant character in HCC, through regulation of CCL5 signaling. DSE mRNA and protein were downregulated frequently in HCC tumors, where these events were associated with advanced tumor stages, metastases, and poor survival. DSE-mediated tumor growth was evaluated in immune-deficient and immune-complement mice models. Restoring DSE expression in HCC cells suppressed tumor growth, as well as decreased IL-1β and CCL5 levels in transplanted tumor tissue. Mechanistic investigations revealed that the expression of DSE altered CCL5 signaling and cell surface binding in HCC cells. Accordingly, DSE suppressed CCL5-induced cell growth, migration, and invasion, whereas silencing of DSE enhanced CCL5-triggered malignant phenotypes. Inhibiting CCR1 activity with BX471 decreased CCL5-induced malignant characters caused by siRNA-mediated knockdown of DSE in HCC cells, establishing the critical role of the CCL5/CCR1 axis in mediating the effects of DSE expression. Taken together, our results suggest that DSE dysregulation contributes to the malignant behavior of HCC cells. This provides novel insight into the significance of DSE in CCL5 signaling and HCC pathogenesis.

KEYWORDS:
CCL5; DS epimerase; Dermatan sulfate; hepatocellular carcinoma; tumor infiltrated lymphocyte

PMID: 30906633
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Select item 30906632
13.
Am J Cancer Res. 2019 Feb 1;9(2):330-346. eCollection 2019.
Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett's associated esophageal adenocarcinoma.
Lyros O1, Lamprecht AK1, Nie L2, Thieme R1, Götzel K1, Gasparri M3, Haasler G3, Rafiee P4, Shaker R2, Gockel I1.
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Abstract
Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/β-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active β-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of β-catenin signaling in EAC in comparison with Barrett's and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline β-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate β-catenin transcription. These findings suggest that the β-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC.

KEYWORDS:
Akt; Barrett's adenocarcinoma; Dickkopf-1; Wnt signaling; esophagus

PMID: 30906632
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Select item 30906631
14.
Am J Cancer Res. 2019 Feb 1;9(2):312-329. eCollection 2019.
MiR-1205 functions as a tumor suppressor by disconnecting the synergy between KRAS and MDM4/E2F1 in non-small cell lung cancer.
Yan H1,2, Chen X1, Li Y1,2, Fan L1,2, Tai Y1,2, Zhou Y1,2, Chen Y1, Qi X1,2, Huang R2,3, Ren J1,2.
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Abstract
Activated KRAS is frequently observed and paralleled by inactivating of tumor suppressors in lung cancer, while the mechanisms remained elusive. Here, our study revealed a microRNA was involved in KRAS overexpression, activation of KRAS signaling and its synergy with inactivating of tumor suppressor genes. miR-1205 was selected by its sequence-dependent inhibition on KRAS and negative clinical correlation with KRAS. A549 and H460 cells carrying mutant KRAS, were sensitive to the growth inhibition and G1/S arrest induced by miR-1205. Target analysis revealed that miR-1205 could simultaneously downregulate the expression levels of MDM4 and E2F1, which were downstream of KRAS and synergistic with KRAS. Silencing of MDM4 or E2F1 inhibited cellular proliferation. MiR-1205 decreased the protein levels of MDM4 and E2F1 via directly binding to the coding sequence of E2F1 and 3'UTR of MDM4. Meanwhile, blocking RAS-MAPK signaling using KRAS siRNA or ERK1/2 inhibitor exerted similar inhibitory effects on MDM4 and E2F1. Forced expression of KRAS partially restored the inhibition of miR-1205 on MDM4 and E2F1. Overexpression of KRAS, MDM4 or E2F1 could partially rescued the growth inhibition of miR-1205 in vitro. More importantly, miR-1205 strongly inhibited the tumor growth of A549 xenografts in nude mice and decreased the protein levels of KRAS, MDM4 and E2F1 in tumor tissues. Together, our study firstly confirmed a potential synergy between KRAS and MDM4/E2F1 which are p53/RB inactivators in non-small cell lung cancer, and identified miR-1205 as a potent destructor of this synergy, making miR-1205 function as a tumor suppressor in vitro and in vivo.

KEYWORDS:
E2F1; KRAS; MDM4; inactivator of tumor suppressor genes; microRNA; oncogene activation

PMID: 30906631
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Select item 30906630
15.
Am J Cancer Res. 2019 Feb 1;9(2):300-311. eCollection 2019.
Long noncoding RNA CASC11 promotes osteosarcoma metastasis by suppressing degradation of snail mRNA.
Song K1, Yuan X2,3, Li G1, Ma M1, Sun J1.
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Abstract
Osteosarcoma (OS) is the most common primary bone tumor in adolescents. Dysregulation of long noncoding RNAs (lncRNAs) is associated with the cancer progression, of which cancer susceptibility candidate 11 (CASC11) has been indicated as an oncogene in several human cancers. However, the underlying mechanisms by which CASC11 contributes to OS metastasis remain undetermined. Here, we found that CASC11 expression in OS tissues was markedly higher than that in noncancerous tissues. Clinical association analysis revealed that high CASC11 expression correlated with clinical stage, distant metastasis and poor prognosis of OS patients. Gain- and loss-of-function assays demonstrated that CASC11 promoted migration, invasion, epithelial-mesenchymal transition (EMT) and metastasis of OS cells in vitro and in vivo. CASC11 associated with the EMT inducer Snail mRNA and increased its stability. Association of CASC11 with Snail mRNA blocked the repressing effect of miR-122, miR-145, miR-211, miR-34a and miR-137 on Snail. Moreover, CASC11-specific siRNAs significantly inhibit tumor metastasis in vivo. Taken together, our findings suggest that CASC11 may be a candidate prognostic biomarker and a novel therapeutic target for OS.

KEYWORDS:
lncRNA; metastasis; microRNA; stability

PMID: 30906630
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Select item 30906629
16.
Am J Cancer Res. 2019 Feb 1;9(2):285-299. eCollection 2019.
E2F1 transactivates IQGAP3 and promotes proliferation of hepatocellular carcinoma cells through IQGAP3-mediated PKC-alpha activation.
Lin M1, Liu Y2,3, Ding X4, Ke Q1, Shi J5, Ma Z4, Gu H4, Wang H1,5, Zhang C3, Yang C1, Fang Z1, Zhou L3, Ye M1,4.
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Abstract
For decades, E2F1 has been recognized as a retinoblastoma protein (RB) binding transcription factor that regulates the cell cycle. E2F1 binds preferentially to RB and accelerates the cell cycle in most cancer cells. However, it is thought that E2F1 modulates cell proliferation in other ways as well. Herein, it has been discovered that in pathological tissues derived from hepatocellular carcinoma (HCC) patients, E2F1 correlates positively with IQGAP3 and that both of these factors are highly expressed (N = 164, R = 0.6716). In addition, a high level of E2F1 or IQGAP3 predicted poor survival in HCC patients. Further study determined that E2F1 transactivates IQGAP3, the GTPase binding protein in MHCC-97H cells. Co-immunoprecipitation analysis indicated that IQGAP3 interacts with PKCδ and competitively inhibits the interaction between PKCδ and PKCα, resulting in phosphorylation of PKCα activation and promotion of cell proliferation. This study reveals that highly expressed E2F1 not only transactivates cell-cycle-related factors but also promotes HCC proliferation by activating the phosphorylation of PKCα.

KEYWORDS:
E2F1; IQGAP3; PKCα activation; cell proliferation; hepatocellular carcinoma

PMID: 30906629
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Select item 30906628
17.
Am J Cancer Res. 2019 Feb 1;9(2):270-284. eCollection 2019.
The positive feedback loop of lncRNA DANCR/miR-138/Sox4 facilitates malignancy in non-small cell lung cancer.
Bai Y1, Zhang G1, Chu H1, Li P1, Li J1.
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Abstract
Non-small cell lung cancer (NSCLC) is one of the most frequent cancers worldwide. The abnormal expression of long non-coding RNAs (lncRNAs) has been reported to be closely associated with the progression of human cancers, including NSCLC. Here, we demonstrated that differentiation antagonizing noncoding RNA (DANCR) was overexpressed in NSCLC tissues. Upregulation of DANCR expression was significantly associated with larger tumor size, advanced TNM stage and lymph node metastasis, and also predicted poor prognoses of patients with NSCLC. Functional experiments showed that DANCR enhanced NSCLC growth and metastasis both in vitro and in vivo. Further investigation revealed that DANCR could compete with the Sox4 mRNA to bind with miR-138, thus affecting Sox4 expression. In addition, we found that Sox4 bound to the promoter regions of DANCR gene to activate DANCR expression, suggesting a positive feedback loop of DANCR/miR-138/Sox4 in NSCLC. Taken together, these results provide a comprehensive analysis of the roles of DANCR as a competing endogenous RNA (ceRNA) in NSCLC progression.

KEYWORDS:
DANCR; Sox4; ceRNA; metastasis

PMID: 30906628
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Select item 30906627
18.
Am J Cancer Res. 2019 Feb 1;9(2):250-269. eCollection 2019.
MicroRNA-940 inhibits glioma progression by blocking mitochondrial folate metabolism through targeting of MTHFD2.
Xu T1, Zhang K1,2, Shi J1, Huang B1,3, Wang X1, Qian K1, Ma T1, Qian T1, Song Z1, Li L1.
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Abstract
The aggressiveness and recurrence of glioma are major obstacles for the treatment of this type of tumor. Further understanding of the molecular mechanisms of glioma is necessary to improve the efficacy of therapy. MicroRNAs have been widely studied in many human cancers. Here, we found that miR-940 was one of the primary downregulated miRNAs in clinical samples and glioma cell lines through bioinformatics analysis and qRT-PCR. Upregulating miR-940 expression significantly inhibited the proliferation and invasion and promoted apoptosis of U87 and U118 cells. In addition, experiments in vivo showed that upregulation of miR-940 expression inhibited xenograft growth. Methylenetetrahydrofolate dehydrogenase (MTHFD2), a dual-functional metabolic enzyme, is involved in the one-carbon metabolism of folate in mitochondria. We found MTHFD2 to be overexpressed in glioma tissues and our clinical samples by qRT-PCR and Western blot assays. Through TargetScan prediction and luciferase assays, we found that miR-940 directly targets MTHFD2. Upregulation of miR-940 expression inhibited the expression of MTHFD2 and led to intracellular one-carbon metabolism dysfunction. Furthermore, the antitumor effects of miR-940 could be attenuated by overexpression of MTHFD2. Together, the results of our study suggest that miR-940 may be a new therapeutic target for the treatment of glioma through targeting of MTHFD2.

KEYWORDS:
MTHFD2; apoptosis; invasion; miR-940; one-carbon metabolism; proliferation

PMID: 30906627
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Select item 30906626
19.
Am J Cancer Res. 2019 Feb 1;9(2):242-249. eCollection 2019.
Interplay between heat shock proteins, inflammation and cancer: a potential cancer therapeutic target.
Ikwegbue PC1, Masamba P1, Mbatha LS1, Oyinloye BE2, Kappo AP1.
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Abstract
The historical relationship between cancer and inflammation has long been evaluated, and dates back to the early work of Virchow (1863), where he hypothesised that chronic inflammation as a direct cause of tissue injury and infection, could actually promote tissue proliferation. At that period in time however, the exact mechanisms that mediated this relationship were little understood. Subsequent studies have since then demonstrated that chronic inflammation plays significant roles in microenvironments, mostly in the progression of tumours, probably, through over-secretion of proinflammatory cytokines and other immune-killing apparatus such as reactive oxygen species (ROS) which cause damage to normal cells leading to DNA damage and increased cellular mutation rates. Recently, the identification of DNA lesion 5-chlorocytosine (5-CIC) created by hypochlorous acid (HOCl) secreted to nullify or kill infectious agents and toll-like receptor 4 (TLR4)-mediated chronic inflammation in the human gut, has become the latest evidence linking inflammation directly to cancer. The key to cellular survival and adaptation under unfavourable or pathological conditions is the expression of heat shock proteins (HSPs) also called molecular chaperones. These proteins play essential roles in DNA repair processes by maintaining membrane integrity, orderliness and stability of client proteins that play prominent roles in DNA repair mechanisms. More so, HSPs have also been shown to modulate the effects of pro-inflammatory/apoptotic cytokines through the inhibition of cascades leading to the generation of ROS-mediated DNA damage, while promoting the DNA repair mechanism, thus playing prominent roles in various stages of DNA repair and cancer progression. Hence, studies targeting HSPs and their inhibitors in inflammation, DNA damage, and repair, could improve current cancer therapeutic efficiency. Here the focus will be on the relationship between HSPs, inflammation and cancer, as well as roles of HSPs in DNA damage response (DDR).

KEYWORDS:
5-chlorocytosine; DNA damage response; Heat shock proteins; cancer; hypochlorous acid; inflammation

PMID: 30906626
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20.
Am J Cancer Res. 2019 Feb 1;9(2):228-241. eCollection 2019.
Target selection of CAR T cell therapy in accordance with the TME for solid tumors.
Liu B1, Yan L1, Zhou M2.
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Abstract
Chimeric antigen receptor-engineered T (CAR T) cell therapy has made great progress in hematological malignancies and resulted in two newly FDA-approved drugs specific for CD19, Kymriah and Yescarta. To some extent, this success is attributable to the appropriately selected antigen, CD19, a cell surface protein that is uniformly and strongly expressed on malignant B cells. This result indicates that a proper CAR target is of great importance to the success of this technique. Another key factor contributing to the success of hematological malignancies can be ascribed to the nonphysical tumor microenvironment (TME). The TME in solid tumors is complicated and has a specific niche favorable for tumor progression with physical barriers, multiple mechanisms of immunosuppression, and a variety of biochemical factors, thus resulting in limited efficacy of CAR T cell therapy in clinical trials with cancer patients. Therefore, the inhospitable solid TME becomes a major hurdle in translating the success of CAR T cell therapy in hematological malignancies to solid tumors. Here, we provide our perspective on how to improve the success of CAR T therapy in solid tumors by focusing on the aspects of target selection and the related TME in CAR T cell design, especially stressing the interplay between them. With four kinds of antigenic CAR targets as examples in this review, we anticipate that the overall consideration of both factors will further expand CAR T cell therapy in clinical trials.

KEYWORDS:
CAR T cell therapy; anti-tumor immunity; solid tumor; target selection; tumor antigen; tumor microenvironment

PMID: 30906625
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