Publications by authors named "Teng Hou"

40 Publications

Nanoparticle-Loaded Polarized-Macrophages for Enhanced Tumor Targeting and Cell-Chemotherapy.

Nanomicro Lett 2020 Oct 27;13(1). Epub 2020 Oct 27.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, People's Republic of China.

Cell therapy is a promising strategy for cancer therapy. However, its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor microenvironments. In this study, the "cell-chemotherapy" strategy was presented to enhance antitumor efficacy. M1-type macrophages, which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability, carried sorafenib (SF)-loaded lipid nanoparticles (M1/SLNPs) were developed. M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously. M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide, and M1/SLNPs were obtained by incubating M1-type macrophages with SLNP. Tumor accumulation of M1/SLNP was increased compared with SLNP (p < 0.01), which proved M1/SLNP could enhance tumor targeting of SF. An increased ratio of M1-type macrophages to M2-type macrophages, and the CD3CD4 T cells and CD3CD8 T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor microenvironments. The tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group (p < 0.01), indicating M1/SLNP exhibited enhanced antitumor efficacy. Consequently, M1/SLNP showed great potential as a novel cell-chemotherapeutic strategy combining both cell therapy and targeting chemotherapy.
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http://dx.doi.org/10.1007/s40820-020-00531-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187668PMC
October 2020

[Horizontal penetration needling method for headache].

Zhongguo Zhen Jiu 2020 Nov;40(11):1193-7

Department of Encephalopathy, Nanjing Hospital of TCM, Nanjing University of Chinese Medicine, Nanjing 210001, Jiangsu Province.

The manipulation and key points of professor -'s horizontal penetration needling method for headache were introduced. This acupuncture method selects local acupoints of head, including occipital acupoint group, temporal acupoint group, frontal acupoint group and vertex acupoint group. The needles are shallowly and horizontally inserted at acupoints, with needle end towards the focus or headache site. The needle retaining time is long (6 h). This method is commonly used in the treatment of migraine, cervicogenic headache and tension-type headache. The manipulation is standard with better repeatability.
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http://dx.doi.org/10.13703/j.0255-2930.20200114-k0001DOI Listing
November 2020

Downregulation of NUDT21 contributes to cervical cancer progression through alternative polyadenylation.

Oncogene 2021 Mar 22;40(11):2051-2064. Epub 2021 Feb 22.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.

Nudix Hydrolase 21 (NUDT21), an alternative polyadenylation (APA)-regulatory protein, exhibits tumor-suppressive effects. However, its role in cervical cancer (CxCa) remains unknown. In the present study, we found that NUDT21 expression was reduced in CxCa tissues and cells, and NUDT21 levels were highly associated with the clinical prognosis of patients with CxCa. Knockdown of NUDT21 promoted CxCa cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and lung metastasis in vivo. Overexpression of NUDT21 produces the opposite effects. Moreover, we performed polyadenylation site sequencing (PAS-Seq) and identified 457 transcripts with lengthened 3' untranslated regions (3' UTRs) upon NUDT21 overexpression. In particular, NUDT21 modulated the expression of several genes involved in fatty acid metabolism and the Wnt and NF-κB signaling pathways in CxCa development. Taken together, our study demonstrated that the APA regulatory effect of NUDT21 is an important mechanism for CxCa suppression.
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http://dx.doi.org/10.1038/s41388-021-01693-wDOI Listing
March 2021

Laparoscopic "reverse 7" ileal ureteral replacement for bilateral extensive ureteral strictures performed completely intracorporeally: the initial experience.

Int Urol Nephrol 2021 May 2;53(5):919-924. Epub 2021 Jan 2.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue No. 1277, Wuhan, 430022, China.

Purpose: To present our initial experience and evaluate the feasibility of the novel technique of completely intracorporeal laparoscopic "reverse 7" ileal ureteral replacement (IUR).

Materials And Methods: Between December 2018 and September 2019, two patients underwent completely intracorporeal laparoscopic "reverse 7" IUR, which were female patients with bilateral extensive ureteral strictures (BEUS) secondary to radical hysterectomy and pelvic lymph node dissection for cervical cancer and postoperative radiotherapy. Antegrade pyelography and retrograde pyelography showed BEUS preoperatively.

Results: The novel technique was performed successfully by the same surgeon without conversion to open surgery. The operating time of each patient was 420 min and 410 min, respectively. Meanwhile, the estimated blood loss of each patient was 120 ml and 100 ml, respectively. There were no major complications during the perioperative period. After ureteral stent was removed, antegrade pyelography postoperatively revealed excellent drainage with the resolution of hydronephrosis in both patients. After removing of ureteral stent and nephrostomy tube, no patients have a complaint about the donor site or the onset of flank pain.

Conclusions: To our knowledge, we present the initial experience with completely intracorporeal laparoscopic "reverse 7" IUR. With initial follow-up outcomes, this novel minimally invasive technique appears to be feasible and efficacious in treating BEUS in carefully selected patients.
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http://dx.doi.org/10.1007/s11255-020-02751-0DOI Listing
May 2021

Charge and Size Dual Switchable Nanocage for Novel Triple-Interlocked Combination Therapy Pattern.

Adv Sci (Weinh) 2020 Sep 4;7(18):2000906. Epub 2020 Aug 4.

Department of Pharmaceutics Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences Shandong University 44 Wenhuaxi Road Jinan Shandong 250012 China.

Combination therapy is a current hot topic in cancer treatment. Multiple synergistic effects elicited by combined drugs are essential in improving antitumor activity. Herein, a pH-triggered charge and size dual switchable nanocage co-loaded with abemaciclib and IMD-0354 (PA/PI-ND) is reported, exhibiting a novel triple-interlocked combination of chemotherapy, immunotherapy, and chemoimmunotherapy. The charge reversal polymer NGR-poly(ethylene glycol)-poly(l-lysine)-dimethylmaleic anhydride (NGR-PEG-PLL-DMA, ND) in PA/PI-ND promotes the pH-triggered charge reversal from negative to positive and size reduction from about 180 to 10 nm in an acidic tumor microenvironment, which greatly enhances cellular uptake and tumor tissue deep penetration. With the PA/PI-ND triple-interlocked combination therapy, the chemotherapeutic effect is enhanced by the action of abemaciclib to induce cell cycle arrest in the G1 phase, together with the reduction in cyclin D levels caused by IMD-0354. The dual anti-tumor promoting immunotherapy is achieved by abemaciclib selectively inhibiting the proliferation of regulatory T cells (Tregs) and by IMD-0354 promoting tumor-associated macrophage (TAM) repolarization from an M2 to M1 phenotype. Furthermore, PA/PI-ND has improved anti-tumor efficiency resulting from the third synergistic effect provided by chemoimmunotherapy. Taken together, PA/PI-ND is a promising strategy to guide the design of future drug delivery carriers and cancer combination therapy.
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http://dx.doi.org/10.1002/advs.202000906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509747PMC
September 2020

Small Morph Nanoparticles for Deep Tumor Penetration via Caveolae-Mediated Transcytosis.

ACS Appl Mater Interfaces 2020 Aug 13;12(34):38499-38511. Epub 2020 Aug 13.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province 250012, People's Republic of China.

The tumor penetration of nanomedicines constitutes a great challenge in the treatment of solid tumors, leading to the highly compromised therapeutic efficacy of nanomedicines. Here, we developed small morph nanoparticles (PDMA) by modifying polyamidoamine (PAMAM) dendrimers with dimethylmaleic anhydride (DMA). PDMA achieved deep tumor penetration via an active, energy-dependent, caveolae-mediated transcytosis, which circumvented the obstacles in the process of deep penetration. PDMA remained negatively charged under normal physiological conditions and underwent rapid charge reversal from negative to positive under acidic conditions in the tumor microenvironment (pH < 6.5), which enhanced their uptake by tumor cells and their deep penetration into tumor tissues and . The deep tumor penetration of PDMA was achieved mainly by caveolae-mediated transcytosis, which could be attributed to the small sizes (5-10 nm) and positive charge of the morphed PDMA. studies demonstrated that PDMA exhibited increased tumor accumulation and doxorubicin-loaded PDMA (PDMA/DOX) showed better antitumor efficacy. Overall, the small morph PDMA for enhanced deep tumor penetration via caveolae-mediated transcytosis could provide new inspiration for the design of anticancer drug delivery systems.
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http://dx.doi.org/10.1021/acsami.0c06872DOI Listing
August 2020

"Layer peeling" co-delivery system for enhanced RNA interference-based tumor associated macrophages-specific chemoimmunotherapy.

Nanoscale 2020 Aug;12(32):16851-16863

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong Province 250012, China.

RNA interference (RNAi)-based immunotherapy combined with chemotherapy has emerged as a promising therapeutic strategy for cancer treatment. The transport of siRNA and small molecular agents from the tumor vasculature to a separate therapeutic target has been impeded by multiple physiological barriers, which has restricted the development of RNAi-based chemoimmunotherapy. A nanotechnology-based co-delivery system was superior in improving the co-localization of gene and drug in the same tumor cell, while a co-delivery system for chemoimmunotherapy was expected to realize xenotype cell-targeting, which means delivering immunotherapy agents and chemotherapy drugs to immune cells and tumor cells, respectively. A multilayer structure co-delivery system was outstanding in crossing these barriers and targeting different cells in tumor tissue. Herein, a "layer peeling" co-delivery system (CDMPR) was developed with co-loaded IKKβ-siRNA and doxorubicin (DOX), in which IKKβ-siRNA was used for RNAi-based tumor associated macrophages (TAMs) polarization for immunotherapy and DOX was used for chemotherapy. A transwell assay in vitro and an immunofluorescence assay in Hepa1-6 tumor-bearing mice indicated that CDMPR exhibited a pH-sensitive disassembly ability in tumor tissue, IKKβ-siRNA was precisely delivered to M2-type TAMs and DOX was internalized into tumor cells. An M2-type TAMs polarization ability study of CDMPR demonstrated that M2-type TAMs could be polarized to M1-type TAMs by CDMPR in vitro and in vivo. In Hepa1-6 tumor-bearing mice, CDMPR exhibited improved antitumor efficiency with M2-type re-polarization ability by the precise delivery of IKKβ-siRNA and DOX to M2-type TAMs and tumor cells, respectively. Consequently, the combination of RNAi-based TAMs polarization and chemotherapy by the "layer peeling" co-delivery system would achieve an enhanced chemoimmunotherapy effect, which provides a novel strategy to improve cancer therapeutic effects.
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http://dx.doi.org/10.1039/d0nr04025hDOI Listing
August 2020

Engineering Thermo-pH Dual Responsive Hydrogel for Enhanced Tumor Accumulation, Penetration, and Chemo-Protein Combination Therapy.

Int J Nanomedicine 2020 1;15:4739-4752. Epub 2020 Jul 1.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong Province 250012, People's Republic of China.

Purpose: Combined chemotherapeutic drug and protein drug has been a widely employed strategy for tumor treatment. To realize both tumor accumulation and deep tumor penetration for drugs with different pharmacokinetics, we propose a structure-transformable, thermo-pH dual responsive co-delivery system to co-load granzyme B/docetaxel (GrB/DTX).

Methods: Thermo-sensitive hydrogels based on diblock copolymers (mPEG--PELG) were synthesized through ring opening polymerization. GrB/DTX mini micelles (GDM) was developed by co-loading these two drugs in pH-sensitive mini micelles, and the GDM-incorporated thermo-sensitive hydrogel (GDMH) was constructed. The thermo-induced gelation behavior of diblock copolymers and the physiochemical properties of GDMH were characterized. GDMH degradation and deep tumor penetration of released mini micelles were confirmed. The pH-sensitive disassembly and lysosomal escape abilities of released mini micelles were evaluated. In vitro cytotoxicity was studied using MTT assays and the in vivo antitumor efficacy study was evaluated in B16-bearing C57BL/6 mice.

Results: GDMH was gelatinized at body temperature and can be degraded by proteinase to release mini micelles. The mini micelles incorporated in GDMH can achieve deep tumor penetration and escape from lysosomes to release GrB and DTX. MTT results showed that maximum synergistic antitumor efficacy of GrB and DTX was observed at mass ratio of 1:100. Our in vivo antitumor efficacy study showed that GDMH inhibited tumor growth in the subcutaneous tumor model and in the post-surgical recurrence model.

Conclusion: The smart-designed transformable GDMH can facilitate tumor accumulation, deep tumor penetration, and rapid drug release to achieve synergistic chemo-protein therapy.
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http://dx.doi.org/10.2147/IJN.S253990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342477PMC
August 2020

Circ_0008532 promotes bladder cancer progression by regulation of the miR-155-5p/miR-330-5p/MTGR1 axis.

J Exp Clin Cancer Res 2020 May 27;39(1):94. Epub 2020 May 27.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, HB, China.

Background: Circular RNAs (circRNAs) have been associated with bladder cancer (BC), but the specific underlying molecular mechanism of their association with BC development has not been fully explored.

Methods: Levels of Circ_0008532, MTGR1 and miR-155-5p/miR-330-5p in bladder cancer cell lines and tissues were determined with quantitative real-time PCR and western blotting assays. In vitro and in vivo assays were performed to investigate the function of circ_0008532 in tumorigenesis in bladder cancer cells. The relationships of Circ_0008532, MTGR1 and miR-155-5p/miR-330-5p were predicted using bioinformatic tools and verified by RNA-FISH, RIP and luciferase assays. The effects of circ_0008532 on the Notch signaling pathway were determined by GSEA analysis and western blotting assay.

Results: We found that circ_0008532 is upregulated in BC cell lines and tissues. Moreover, overexpression of circ_0008532 promotes, and silencing of circ_0008532 inhibits the capacity for invasive in BC cells. In addition, circ_0008532 can directly interact with miR-155-5p and miR-330-5p as an miRNA sponge which mediates the expression of the miR-155-5p/miR-330-5p target gene MTGR1 and downstream Notch signaling.

Conclusions: Circ_0008532 may act as an oncogene in BC through a novel circ_0008532/miR-155-5p, miR-330-5p /MTGR1/Notch pathway axis, which in turn may provide potential biomarkers and a therapeutic target for the management of bladder cancer.
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http://dx.doi.org/10.1186/s13046-020-01592-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251916PMC
May 2020

NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation.

Theranostics 2019 23;9(24):7156-7167. Epub 2019 Sep 23.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Nudix Hydrolase 21 (NUDT21) is a crucial mediator involved in alternative polyadenylation (APA), and this molecule has been reported to be a tumor suppressor in human cancers. However, neither the role NUDT21 plays in bladder cancer (BC) nor the mechanisms which are involved have been investigated. Expression levels of NUDT21 in BC were evaluated with real-time PCR, western blotting, and immunohistochemistry (IHC). and assays were performed to investigate the function of NUDT21 in tumorigenesis in bladder cancer cells. The TOP/FOP flash reporter assay, western blot, and global APA site profiling analysis were used to identify the pathway which mediates the biologic roles of NUDT21 in BC. NUDT21 expression is reduced in BC tissue and cells, and BC patients with lower NUDT21 expression have shorter overall and recurrent-free survival than patients with higher NUDT21 expression. NUDT21 ectopic expression or knockdown respectively profoundly inhibited or promoted the capacity of BC cells for proliferation, migration and invasion. We also identified a number of genes with shortened 3'UTRs through modulation of NUDT21 expression, and further characterized the NUDT21-regulated genes ANXA2 and LIMK2. We found NUDT21 modulates the expression of ANXA2 and LIMK2 in the Wnt/β-catenin and NF-κB signaling pathways. These findings show NUDT21 plays a crucial role in BC progression, at least in part through ANXA2 and LIMK2 which act by alternative polyadenylation. NUDT21 may thus have potential as a diagnostic and therapeutic target in treatment of BC.
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http://dx.doi.org/10.7150/thno.36030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831288PMC
September 2020

Selective targeting of tumor cells and tumor associated macrophages separately by twin-like core-shell nanoparticles for enhanced tumor-localized chemoimmunotherapy.

Nanoscale 2019 Aug 15;11(29):13934-13946. Epub 2019 Jul 15.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province 250012, People's Republic of China.

Tumor associated macrophage (TAM)-based immunotherapy has been presented as a promising strategy in cancer therapy. The combination of TAM-based immunotherapy with sorafenib (SF) could be conceivably quite more effective in hepatocellular carcinoma (HCC) treatment. A co-delivery system was superior in improving the co-accumulation of two drugs in tumor tissues for chemoimmunotherapy, while in the case of selective targeting of separated cells such as tumor cells and immune cells, a novel targeted co-delivery strategy was badly required. In this study, twin-like core-shell nanoparticles (TCN) were developed for synchronous biodistribution and separated cell targeting delivery of SF and TAM re-polarization agents IMD-0354 to cancer cells and TAM to enhance tumor-localized chemoimmunotherapy, respectively. First of all, SF loaded cationic lipid-based nanoparticles (SF-CLN) and mannose-modified IMD-0354 loaded cationic lipid-based nanoparticles (M-IMD-CLN) were prepared, respectively. SF on the surface of SF-CLN and mannose on the M-IMD-CLN were regarded as targeting ligands for selective targeting delivery of SF-CLN and M-IMD-CLN to cancer cells and TAM separately. Then, pH-responsive charge reversal polymer O-carboxymethyl-chitosan (CMCS) was coated on the SF-CLN and M-IMD-CLN to obtain twin-like CMCS/SF-CLN and CMCS/M-IMD-CLN, respectively. The results of cellular uptake assay on Hepa1-6 cells and RAW 264.7 cells in vitro, respectively, as well as the results of tumor tissue distribution of SF and IMD-0354 in vivo suggested that CMCS/SF-CLN and CMCS/M-IMD-CLN exhibited similar properties in vitro and synchronous biodistribution in vivo, and were efficient at separated cell targeting delivery. What's more, the results of antitumor efficiency in vivo and phenotype analysis of TAM in tumor tissues proved that CMCS/SF-CLN and CMCS/M-IMD-CLN exhibited superior synergistic antitumor efficacy and M2-type TAM polarization ability compared with SF treatment in Hepa1-6 tumor bearing mice. Consequently, TCN which was the combination of co-administration and nano-drug delivery systems has great potential to be used in tumor-localized chemoimmunotherapy in clinics.
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http://dx.doi.org/10.1039/c9nr03374bDOI Listing
August 2019

Correction: CLCA4 inhibits bladder cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT pathway.

Oncotarget 2019 01 29;10(9):1010. Epub 2019 Jan 29.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

[This corrects the article DOI: 10.18632/oncotarget.21724.].
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http://dx.doi.org/10.18632/oncotarget.26656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398175PMC
January 2019

MicroRNA‑122 downregulates Rho‑associated protein kinase 2 expression and inhibits the proliferation of prostate carcinoma cells.

Mol Med Rep 2019 May 27;19(5):3882-3888. Epub 2019 Feb 27.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

MicroRNA‑122 (miR‑122) has been reported to be involved in the pathogenesis of several types of malignancies; however, its role in prostate carcinoma remains unknown. Thus, the current study aimed to investigate the functionality of miR‑122 in prostate carcinoma. Clinical data of 54 patients with prostate carcinoma who were diagnosed and treated in Union Hospital (Wuhan, China) between January 2011 and January 2013 were retrospectively analyzed. The expression levels of miR‑122 and Rho‑associated protein kinase 2 (ROCK2) in prostate tumor and adjacent healthy tissues of patients, as well as in the serum of prostate carcinoma patients and healthy controls, were detected by reverse transcription‑quantitative polymerase chain reaction. Receiver operating characteristic curve and survival curve analyses were used to examine the diagnostic and prognostic values of serum miR‑122 for prostate carcinoma. In addition, miR‑122 mimic was transfected into prostate carcinoma cells, and the effects on cell proliferation and ROCK2 expression were explored by Cell Counting Kit‑8 and western blot assays, respectively. It was observed that miR‑122 was downregulated and ROCK2 was upregulated in tumor tissues as compared with their levels in adjacent healthy tissues. miR‑122 level in the serum was also markedly lower in prostate carcinoma patients in comparison with that in healthy controls. Furthermore, a low serum level of miR‑122 was found to effectively distinguish the prostate carcinoma patients from healthy controls and to be an indicator of poor survival. In prostate carcinoma cells, miR‑122 overexpression inhibited the proliferation and the expression of ROCK2. Taken together, miR‑122 may inhibit the proliferation of prostate carcinoma cells possibly by downregulating ROCK2 expression.
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http://dx.doi.org/10.3892/mmr.2019.9995DOI Listing
May 2019

Carboplatin-loaded SMNDs to reduce GSH-mediated platinum resistance for prostate cancer therapy.

J Mater Chem B 2018 Nov 17;6(43):7004-7014. Epub 2018 Oct 17.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, China.

Glutathione (GSH)-mediated drug resistance can strongly weaken the therapeutic efficiency of platinum(ii). Therapeutic platforms developed based on small-molecule-based nanodrugs (SMNDs) have gained great attention due to their unique properties. Herein, a novel SMND of carboplatin-lauric acid nanoparticles (CBP-LA NPs) was developed for the first time to reduce GSH-mediated platinum resistance and improve the antitumor efficiency of platinum(ii). A CBP-LA conjugate was synthesized and CBP-LA NPs were prepared. Intracellular glutathione determination and intracellular Pt-DNA adduct assay were performed. Then the cellular cytotoxicity, cellular uptake, targeted biodistribution and in vivo antitumor efficacy of CBP-LA NPs were investigated. The CBP-LA conjugate could self-assemble into nanoparticles with small, uniform size and high drug loading (48%). The CBP-LA NPs exhibited a low critical aggregation concentration of 1.4 μg mL and outstanding plasma stability in vitro. Under reduced conditions, the CBP-LA NPs showed redox-responsive behavior. The intracellular glutathione determination and the Pt-DNA adduct assay revealed that CBP-LA NPs could reduce the intracellular GSH levels and improve the efficiency of platinum chelating with DNA, which would overcome GSH-mediated platinum(ii) resistance. The cellular uptake study revealed that CBP-LA NPs were internalized by tumor cells, which was very beneficial for improving the therapeutic efficiency. Furthermore, an in vivo study demonstrated that CBP-LA NPs significantly enhanced drug accumulation at tumor sites and improved antitumor efficiency (p < 0.05) compared to the CBP solution group. This study suggests that CBP-LA NPs are a potential formulation to enhance prostate cancer therapy.
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http://dx.doi.org/10.1039/c8tb01721bDOI Listing
November 2018

RSPO3 promotes the aggressiveness of bladder cancer via Wnt/β-catenin and Hedgehog signaling pathways.

Carcinogenesis 2019 04;40(2):360-369

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan HB, China.

R-spondin 3 (RSPO3) is a secreted protein that associates directly with Wnt/β-catenin signaling. However, its functional contribution and prognostic value in human bladder cancer remain unclear. Here, we showed that RSPO3 is upregulated in bladder cancer tissues and cells, and high expression of RSPO3 correlates with advanced clinicopathological features, poor prognosis and disease progression in bladder cancer patients. Furthermore, we observed that ectopic expression or knockdown of RSPO3 profoundly promoted or inhibited, respectively, the invasive ability of bladder cancer cells. Mechanistically, RSPO3 promoted bladder cancer progression via mediating the Wnt/β-catenin and Hedgehog signaling pathways. These findings demonstrate, for the first time, that RSPO3 exhibited a tumor-promoting effect in bladder cancer cells through activation of Wnt/β-catenin and Hedgehog signaling pathways. Thus, RSPO3 may be served as a potential therapeutic target for bladder cancer treatment.
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http://dx.doi.org/10.1093/carcin/bgy140DOI Listing
April 2019

Prognostic Implication of Urothelial Stem Cell Markers Differs According to Primary Tumour Location in Non-Muscle-Invasive Bladder Cancer.

Cell Physiol Biochem 2018 16;48(6):2364-2373. Epub 2018 Aug 16.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background/aims: This study aimed to validate the value of urothelial stem cell (USC) markers ΔNp63, integrin β4, CD47, and CD44v6 in predicting the prognosis of non-muscle invasive bladder cancer (NMIBC) located in different anatomic regions of bladder.

Methods: The study reviewed the clinicopathologic data of 169 patients with NMIBC. Using real-time PCR and immunohistochemistry, the expression of ΔNp63, integrin β4, CD47, and CD44v6 in archived specimens of patients with NMIBC were validated. Kaplan-Meier analysis and Cox proportional hazards model were used to assess the prognostic impact of USC markers for recurrent-free survival (RFS).

Results: The Real-time PCR data showed that the expression of USC markers were higher in tumors located in the trigone and posterior wall than that in other regions of bladder (P< 0.05). Statistical analysis showed that high expression of ΔNp63 was correlated with tumor stage (P=0.023) and tumor size (P=0.001), that high expression of integrin β4 was correlated with tumor stage (P=0.026), tumor grade (P=0.005) and tumor size (P=0.003), and that high integrin β4, CD47, and CD44v6 expression were significantly associated with tumor recurrence (P=0.032, P=0.010, and P=0.043, respectively). Moreover, high expression of ΔNp63 and integrin β4 was correlated with poor RFS in patients with tumors located in the trigone (P=0.025 and P=0.023, respectively). High expression of integrin β4, CD47, and CD44v6 was correlated with poor RFS in patients with tumors in the posterior wall (P=0.017, P=0.033 and P=0.047, respectively). High expression of integrin β4 and CD47 was correlated with poor RFS in patients with tumors in the trigone/posterior wall area (P=0.002 and P=0.005, respectively).

Conclusion: Our results suggest that USC markers are linked with poor prognosis of NMIBC patients, especially in patients with tumors in the trigone and posterior wall.
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http://dx.doi.org/10.1159/000492652DOI Listing
September 2018

Leupaxin Promotes Bladder Cancer Proliferation, Metastasis, and Angiogenesis Through the PI3K/AKT Pathway.

Cell Physiol Biochem 2018 5;47(6):2250-2260. Epub 2018 Jul 5.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background/aims: Leupaxin (LPXN) is a member of the paxillin protein family. Several studies have reported that LPXN regulates cancer development; however, the role of LPXN in bladder cancer remains unknown.

Methods: The expression of LPXN in bladder cancer cells and tissues was determined by real-time PCR, western blotting, and immunohistochemistry, respectively. The biological role of LPXN in bladder cancer cell proliferation, invasion, and angiogenesis was explored both in vitro and in vivo.

Results: LPXN expression was elevated in bladder cancer tissues and cell lines compared to adjacent non-tumor tissues and normal urothelial cells. High LPXN expression was correlated with large tumor size, advanced tumor stage, and poor survival in bladder cancer patients. Overexpression of LPXN significantly promoted the proliferation, invasion, and angiogenesis of bladder cancer cells, while suppressing LPXN had the opposite effects. The impact on tumor progression was abolished by inhibiting PI3K/ AKT signaling pathway. We further demonstrated that LPXN probably up-regulated S100P via the PI3K/AKT pathway.

Conclusions: LPXN may facilitate bladder cancer progression by upregulating the expression of S100P via PI3K/AKT pathway. These results provide a novel insight into the role of LPXN in tumorigenesis and progression of bladder cancer and potential therapeutic target of bladder cancer.
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http://dx.doi.org/10.1159/000491536DOI Listing
August 2018

Loss of Fezf2 promotes malignant progression of bladder cancer by regulating the NF-κB signaling pathway.

Lab Invest 2018 09 20;98(9):1225-1236. Epub 2018 Jun 20.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 43002, China.

Forebrain embryonic zinc finger 2 (Fezf2) is an evolutionarily conserved zinc finger transcription repressor. It has been reported to be a tumor suppressor; however, neither the role that Fezf2 plays in bladder cancer nor the mechanisms involved have been investigated. In this study, we showed that Fezf2 expression is downregulated in bladder cancer tissues and cell lines compared to adjacent non-tumor tissues and normal urothelial cells. We also retrospectively analyzed the association between Fezf2 and various clinicopathologic characteristics in 196 bladder cancer patients, and showed that low expression of Fezf2 is correlated with larger tumor size, advanced tumor stage, and poor clinical prognosis. Moreover, we found that overexpression of Fezf2 significantly inhibited the proliferation, growth, migration, and invasion of bladder cancer cells, and attenuated angiogenesis, while knockdown of Fezf2 had the opposite effect. Fezf2 suppressed bladder cancer aggressiveness by activating the NF-κB signaling pathway. These findings suggest that Fezf2 holds promise as a prognostic biomarker, and provide a putative mechanism for bladder cancer progression.
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http://dx.doi.org/10.1038/s41374-018-0077-9DOI Listing
September 2018

CLCA4 inhibits bladder cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT pathway.

Oncotarget 2017 Nov 9;8(54):93001-93013. Epub 2017 Oct 9.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.

Calcium activated chloride channel A4 (CLCA4), a tumor suppressor, was shown to contribute to the progression of several human cancers, while its role in bladder carcinoma remains unclear. In this study, we showed CLCA4 expression was down-regulated in bladder carcinoma tissues and cells compared to adjacent non-tumor tissues and normal urothelial cells. Low CLCA4 expression was correlated with larger tumor size, advanced tumor stage, and poor prognosis in bladder carcinoma patients. Overexpression of CLCA4 profoundly attenuated the proliferation, growth, migratory and invasive capabilities of bladder cancer cells, whereas CLCA4 knockdown had the opposite effect. Mechanistically, CLCA4 is involved in PI3K/AKT signaling and its downstream molecules can promote bladder cancer cell proliferation. Additionally, CLCA4 could mediate the migration and invasion of bladder cancer cells by regulating epithelial-mesenchymal transition and PI3K/Akt activation. This study suggests that CLCA4 may represent a promising prognostic biomarker for bladder cancer and provides a possible mechanism for bladder cancer growth and invasion.
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http://dx.doi.org/10.18632/oncotarget.21724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696239PMC
November 2017

HBO1 promotes cell proliferation in bladder cancer via activation of Wnt/β-catenin signaling.

Mol Carcinog 2018 Jan 2;57(1):12-21. Epub 2017 Sep 2.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Histone acetyltransferase binding to ORC1 (HBO1), a histone acetyltransferase, was recently identified as an oncoprotein; however, its role in bladder cancer remains unknown. In this study, we showed that HBO1 was highly expressed at both the mRNA and the protein levels in bladder cancer. HBO1 expression was associated with the clinical features of human bladder cancer, including tumor size (P = 0.018) and T (P = 0.007) classifications. Patients with higher HBO1 expression had shorter recurrence-free survival time, whereas patients with lower HBO1 expression had better survival time. Moreover, we found that ectopic overexpression of HBO1 promoted, whereas HBO1 silencing inhibited tumor growth in bladder cancer cells both in vitro and in vivo. We further demonstrated that upregulation of HBO1 activated the Wnt/β-catenin signaling pathway and led to nuclear localization of β-catenin and upregulation of downstream targets of of Wnt/β-catenin signaling. These findings suggest that HBO1 plays a key role in the progression of bladder cancer via the Wnt/β-catenin pathway, and may serve as a potential therapeutic target for the treatment of bladder cancer.
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http://dx.doi.org/10.1002/mc.22715DOI Listing
January 2018

Expression of COL6A1 predicts prognosis in cervical cancer patients.

Am J Transl Res 2016 15;8(6):2838-44. Epub 2016 Jun 15.

State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine Guangzhou, GD 510060, China.

COL6A1 has been shown to play an important role in tumor initiation and progression. The present study is to investigate the clinical significance of COL6A1 in cervical cancer. In this study, the COL6A1 expression levels in 10 paired cervical cancer tissues and the adjacent non-tumor tissues were examined by real-time PCR. The expression of COL6A1 protein was examined in 162 cervical cancer samples by immunohistochemistry, and the correlation of COL6A1 expression with clinicopathologic factors was analyzed. The overall and recurrent-free survival rates were estimated using Kaplan-Meier method and compared with the log-rank test. The prognostic analysis was carried out with multivariate Cox regressions model. The result showed that COL6A1 expression was up-regulated in cervical cancer tissues in compared with that in non-tumor tissues. High expression of COL6A1 was significantly correlated with FIGO stage (P<0.001), tumor size (P=0.025) and lymph node metastasis (P=0.028) of the disease. Moreover, survival analysis showed that high expression of COL6A1 was significantly associated with poorer overall (OS) and recurrent free (RFS) survival (p=0.004 and =0.001, respectively) of cervical cancer patients. Multivariate analysis suggested that COL6A1 expression was an independent prognostic marker of cervical cancer (P=0.029). Thus, COL6A1 may serve as an oncogene in the initiation and progression of cervical cancer, and as a predictor of poor prognosis in cervical cancer patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931178PMC
July 2016

Musashi-2 promotes migration and invasion in bladder cancer via activation of the JAK2/STAT3 pathway.

Lab Invest 2016 09 20;96(9):950-8. Epub 2016 Jun 20.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Musashi-2 (Msi2) is considered to have a crucial role in regulating various key cellular functions. However, the clinical significance and biological role of Msi2 in bladder cancer remains unknown. We examined the expression of Msi2 in bladder cancer cell lines in 167 clinical samples and the biological role of Msi2 in bladder cancer cells. Western blotting was used to investigate the possible mechanism of Msi2-induced migration and invasion in bladder cancer. Msi2 was significantly upregulated in bladder cancer cells and tissues compared with normal bladder urothelial cells and tissues. Immunohistochemical analysis revealed high expression of Msi2 in 57 of 167 (34.1%) bladder cancer specimens. Statistical analysis showed a significant correlation of Msi2 expression with advanced clinical stage, lymph node metastasis, and poor prognosis. Overexpression and ablation of Msi2 promoted and inhibited, respectively, the migration and invasion of bladder cancer cells. Furthermore, we found that Msi2 activated the JAK2/STAT3 pathway and promoted expression of genes downstream of JAK2/STAT3 in bladder cancer. This study demonstrates that Msi2 can induce bladder cancer cell migration and invasion by activating the JAK2/STAT3 pathway, and that Msi2 may be a valuable prognostic biomarker for bladder cancer patients.
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http://dx.doi.org/10.1038/labinvest.2016.71DOI Listing
September 2016

Laparoscopic onlay lingual mucosal graft ureteroplasty for proximal ureteral stricture: initial experience and 9-month follow-up.

Int Urol Nephrol 2016 Aug 26;48(8):1275-1279. Epub 2016 Apr 26.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Purpose: We present our initial experience and 9-month outcomes of the novel technique of laparoscopic onlay lingual mucosal graft ureteroplasty for proximal ureteral stricture.

Materials And Methods: In June 2015, transperitoneal laparoscopic onlay lingual mucosal graft ureteroplasty was performed on a male patient with proximal stricture of the left ureter. The patient complained with left frank pain. Severe hydronephrosis and proximal ureteral dilatation were noted through ultrasonography and CT scan. The length of upper ureteral stricture was 30 mm including 10-mm occlusion. A 46 mm in length and 15 mm in width lingual mucosa graft was harvested from the ventral of the tongue and placed in the strictured ureter as a ventral onlay for laparoscopic ureteroplasty. Operative time, intraoperative, and postoperative complications were well recorded. Follow-up was performed with renal ultrasound, CT scan, and nuclear scan renography as well as clinical assessment of symptoms.

Results: The new technique was performed successful without intraoperative and postoperative complications. Neither hydronephrosis nor proximal ureteral dilatation in the left side was found through ultrasonography 3, 6, 9 months and CT scan 6 month postoperatively. The left renal function, glomerular filtration rate, had a recovery from 9.6 ml/min preoperatively to 14.0 ml/min at 6-month follow-up, and the patient has no complaints about the donor site and flank pain.

Conclusions: To our knowledge, we present the initial experience with laparoscopic onlay lingual mucosal graft ureteroplasty for proximal ureteral stricture. With 9-month outcomes, the new technique appears to be an excellent option for proximal ureteral stricture.
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http://dx.doi.org/10.1007/s11255-016-1289-9DOI Listing
August 2016

B3GNT3 Expression Is a Novel Marker Correlated with Pelvic Lymph Node Metastasis and Poor Clinical Outcome in Early-Stage Cervical Cancer.

PLoS One 2015 28;10(12):e0144360. Epub 2015 Dec 28.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-Sen University, Guangzhou, People's Republic of China.

Background: The β1,3-N-acetylglucosaminyltransferase-3 gene (B3GNT3) encodes a member of the B3GNT family that functions as the backbone structure of dimeric sialyl-Lewis A and is involved in L-selectin ligand biosynthesis, lymphocyte homing and lymphocyte trafficking. B3GNT3 has been implicated as an important element in the development of certain cancers. However, the characteristics of B3GNT3 in the development and progression of cancer remain largely unknown. Thus, our study aimed to investigate the expression pattern and the prognostic value of B3GNT3 in patients with early-stage cervical cancer.

Methods: The mRNA and protein levels of B3GNT3 expression were examined in eight cervical cancer cell lines and ten paired cervical cancer tumors, using real-time PCR and western blotting, respectively. Immunohistochemistry (IHC) was used to analyze B3GNT3 protein expression in paraffin-embedded tissues from 196 early-stage cervical cancer patients. Statistical analyses were applied to evaluate the association between B3GNT3 expression scores and clinical parameters, as well as patient survival.

Results: B3GNT3 expression was significantly upregulated in cervical cancer cell lines and lesions compared with normal cells and adjacent noncancerous cervical tissues. In the 196 cases of tested early-stage cervical cancer samples, the B3GNT3 protein level was positively correlated with high risk TYPES of human papillomavirus (HPV) infection (P = 0.026), FIGO stage (P < 0.001), tumor size (P = 0.025), tumor recurrence (P = 0.004), vital status (P < 0.001), concurrent chemotherapy and radiotherapy (P = 0.016), lymphovascular space involvement (P = 0.003) and most importantly, lymph node metastasis (P = 0.003). Patients with high B3GNT3 expression had a shorter overall survival (OS) and disease-free survival (DFS) compared with those with low expression of this protein. Multivariate analysis suggested that B3GNT3 expression is an independent prognostic indicator for cervical cancer patients.

Conclusions: Our study demonstrated that elevated B3GNT3 expression is associated with pelvic lymph node metastasis and poor outcome in early-stage cervical cancer patients. B3GNT3 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692472PMC
August 2016

Upregulation of centrosomal protein 55 is associated with unfavorable prognosis and tumor invasion in epithelial ovarian carcinoma.

Tumour Biol 2016 May 28;37(5):6239-54. Epub 2015 Nov 28.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gynecologic Oncology, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

Centrosomal protein 55 (CEP55) is a cell cycle regulator implicated in development of certain cancers. However, characteristics of CEP55 expression and its clinical/prognostic significance are unclear in human epithelial ovarian carcinoma (EOC). Therefore, we investigated the expression and clinicopathological significance of CEP55 in patients with EOC and its role in regulating invasion and metastasis of ovarian cell lines. CEP55 mRNA and protein expression levels were detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC). Potential associations of CEP55 expression scores with clinical parameters and patient survival were evaluated. CEP55 function was investigated further using RNA interference, wound healing assay, transwell assay, immunofluorescence analysis, qRT-PCR, and Western blotting. CEP55 was significantly upregulated in ovarian cancer cell lines and lesions compared with normal cells and adjacent noncancerous ovarian tissues. In the 213 EOC samples, CEP55 protein levels were positively correlated with clinical stage (P < 0.001), lymph node metastasis (P < 0.001), intraperitoneal metastasis (P < 0.001), tumor recurrence (P < 0.001), differentiation grade (P < 0.001), residual tumor size (P < 0.001), ascites see tumor cells (P = 0.020), and serum CA153 level (P < 0.001). Moreover, patients with aberrant CEP55 protein expression showed tendencies to receive neoadjuvant chemotherapy (P < 0.001) and cytoreductive surgery (P = 0.020). By contrast, no significant correlation was detected between the protein levels and patient age, histological type, or serum CA125, CA199, CA724, NSE, CEA, and β-HCG levels. Patients with high CEP55 protein expression had shorter overall survival and disease-free survival compared with those with low CEP55 expression. Multivariate analysis implicated CEP55 as an independent prognostic indicator for EOC patients. Additionally, downregulation of CEP55 in ovarian cancer cells remarkably inhibited cellular motility and invasion. Aberrant CEP55 expression may predict unfavorable clinical outcomes in EOC patients and play an important role in regulating invasion in ovarian cancer cells. Thus, CEP55 may serve as a prognostic marker and therapeutic target for EOC.
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http://dx.doi.org/10.1007/s13277-015-4419-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875171PMC
May 2016

Putative stem cell markers in cervical squamous cell carcinoma are correlated with poor clinical outcome.

BMC Cancer 2015 Oct 24;15:785. Epub 2015 Oct 24.

State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, GD, 510060, China.

Background: The aim of this study was to elucidate the value of putative cancer stem cell markers Musashi-1, ALDH1, Sox2, and CD49f in predicting the prognosis in cervical squamous cell carcinoma (CSCC).

Methods: Real-time PCR and immunohistochemistry staining was performed to examine Musashi-1, ALDH1, Sox2, and CD49f expression in archived specimens of CSCC patients with postoperative chemotherapy. Kaplan-Meier analysis and Cox proportional hazards model were used to assess the prognostic impact of CSC markers for overall survival (OS) and recurrent-free survival (RFS).

Results: The Real-time PCR data showed that the expression of all markers were increased in CSCC tissues compared with in paired normal cervical tissues (P < 0.05). The IHC result showed that high expression of Msi1, ALDH1, Sox2, and CD49f was found in 25.7%, 43.0%, 62.0% and 29.0% CSCC samples, respectively. Moreover, high expression of Msi1 (P = 0.033 and P = 0.003, respectively), ALDH1 (P = 0.015 and P = 0.002, respectively), and Sox2 (P = 0.005 and P = 0.003, respectively), and low expression of CD49f (P = 0.027 and P = 0.025, respectively) were correlated with poor OS and PFS in CSCC patients. Interestingly, tumors with Msi1(high)/CD49f(low) expression had the poorest prognosis according to Msi1/CD49f stratification. In multivariate Cox regression analysis, Sox2 expression (P = 0.047 and P = 0.018, respectively), ALDH1 expression (P = 0.013 and P = 0.003, respectively), and CD49f expression (P = 0.008 and P = 0.003, respectively) were independent prognostic markers for both OS and RFS.

Conclusions: Our results suggest that cancer stem cell markers are linked with poor prognosis of CSCC patients.
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http://dx.doi.org/10.1186/s12885-015-1826-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619529PMC
October 2015

C14ORF166 overexpression is associated with pelvic lymph node metastasis and poor prognosis in uterine cervical cancer.

Tumour Biol 2016 Jan 29;37(1):369-79. Epub 2015 Jul 29.

Department of Gynecologic Oncology; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

C14ORF166 (chromosome 14 open reading frame 166) is a transcriptional repressor related to the regulation of centrosome architecture. However, the role of C14ORF166 in the development and progression of cancer remains largely unknown. The aim of this study was to investigate the expression and clinicopathological significance of C14ORF166 in cervical cancer. C14ORF166 expression was analyzed using quantitative real-time PCR (RT-PCR) and Western blotting in cervical cancer cell lines and eight paired cervical cancer samples and the adjacent normal tissues. Immunohistochemistry was used to analyze C14ORF166 protein expression in 148 clinicopathologically characterized cervical cancer specimens. Statistical analyses were performed to evaluate the relationship between the expression of C14ORF166 and clinicopathologic features and prognosis. C14ORF166 mRNA and protein expression were significantly upregulated in cervical cancer cell lines and tissue samples (P < 0.05). Immunohistochemical analysis revealed a high expression of C14ORF166 was observed in 39.9 % (59/148) of the cervical cancer specimens; the remaining samples expressed low levels or did not express any detectable C14ORF166. The chi-square test indicated that high-level expression of C14ORF166 was significantly associated with International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001), vital status (P = 0.026), tumor size (P = 0.034), serum squamous cell carcinoma antigen level (SCC-Ag; P = 0.035), and pelvic lymph node metastasis (P < 0.001). Patients with highly expressed C14ORF166 showed a tendency to receive postoperative chemotherapy (P = 0.005) and postoperative radiation (P = 0.008). Furthermore, high C14ORF166 expression was associated with poorer overall survival compared to low C14ORF166 expression, and C14ORF166 was a significant prognostic factor in univariate and multivariate analysis (P < 0.05). High C14ORF166 expression had prognostic value for poor outcome in cervical cancer. C14ORF166 may represent a biomarker of pelvic lymph node metastasis and enable the identification of high-risk patients along with selection of appropriate treatment strategies.
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http://dx.doi.org/10.1007/s13277-015-3806-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841849PMC
January 2016

Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling.

Mol Med Rep 2015 Sep 14;12(3):3249-3256. Epub 2015 May 14.

Department of Gynecology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.

Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phospho‑Src-Y416 (p‑Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V‑fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of p‑Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p‑Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated anti‑ovarian cancer properties, by downregulating p‑Src expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25‑0.93 and 0.31‑0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated anti‑ovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian cancer cells appeared to be mediated by the Src pathway.
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http://dx.doi.org/10.3892/mmr.2015.3784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526065PMC
September 2015

URG4 overexpression is correlated with cervical cancer progression and poor prognosis in patients with early-stage cervical cancer.

BMC Cancer 2014 Nov 26;14:885. Epub 2014 Nov 26.

Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou 510060, PR China.

Background: Upregulator of cell proliferation 4 (URG4) has been implicated in the oncogenesis of certain cancers. However, the correlation between URG4 expression and clinicopathological significance in human cancer remains unclear. Therefore, this study investigated its expression and clinicopathological significance in cervical cancer patients.

Methods: URG4 expression was examined using quantitative PCR (qPCR) and western blotting in normal cervical epithelial cells, cervical cancer cells, and eight matched pairs of cervical cancer tissues and adjacent noncancerous tissues from the same patient. In addition, immunohistochemistry (IHC) was used to examine URG4 expression in paraffin-embedded tissues from 167 cervical cancer patients (FIGO stages Ib1-IIa2). Statistical analyses were performed to evaluate associations between URG4 expression and prognostic and diagnostic factors.

Results: URG4 was significantly upregulated in the cervical cancer cell lines and tissues compared with the normal cells and adjacent noncancerous cervical tissues. IHC revealed high URG4 expression in 59 out of the 167 (35.13%) cervical cancer specimens. Its expression was significantly correlated with clinical stage (P < 0.0001), tumour size (P = 0.012), T classification (P = 0.023), lymph node metastasis (P = 0.001) and vaginal involvement (P = 0.002). Patients with high URG4 expression, particularly those who received concurrent chemotherapy and radiotherapy (P < 0.0001), showed a shorter overall survival (OS) and disease-free survival (DFS) compared to those with the low expression of this protein. Multivariate analysis revealed that URG4 expression is an independent prognostic factor for cervical cancer patients.

Conclusions: Our results demonstrated that elevated URG4 protein expression is associated with a poor outcome in patients with early-stage cervical cancer. URG4 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.
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http://dx.doi.org/10.1186/1471-2407-14-885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259088PMC
November 2014

Aberrant differentiation of urothelial cells in patients with ureteropelvic junction obstruction.

Int J Clin Exp Pathol 2014 15;7(9):5837-45. Epub 2014 Aug 15.

Department of Urology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology Wuhan 430022, China.

Aim: To investigate the urothelial changes in the pathogenesis of ureteropelvic junction obstruction (UPJ-O).

Methods: A total of 12 patients of UPJ-O were respectively studied. The expression of Annexin A7, Annexin A11, EGFR, Keratin 5, uroplakin III, and SMA in the urothelium of obstructed UPJ segment and of the normal ureter below the obstructed segment were determined by immunofluorescence. Transmission electron microscopy was used to determine the morphological changes in UPJ epithelium in compared to normal ureteral epithelium.

Results: We found that Annexin A7, Annexin A11, EGFR, Keratin 5, and SMA were upregulated, while uroplakin III was downregulated in the urothelium of UPJ-O patients. Furthermore, ultrastructural analyses showed that intercellular spaces between urothelial cells were dilated and the number of microvilli on superficial cells was increased in UPJ-O patients.

Conclusions: We propose that a disrupted urothelial barrier in UPJ-O may results in urothelial inflammatory response and truncated differentiated urothelial cells, which may play an important role in the development and pathogenesis of UPJO.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203196PMC
July 2015