Shengtao Zhou

Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde?

Autophagy is an evolutionarily conserved mechanism for intracellular substance degradation, responsible for the recycling of metabolic substances and the maintenance of intracellular stability. It has early been demonstrated to play a significant role in tumorigenesis, but whether it acts as a promoter or a suppressor during tumorigenesis seems to be context-specific. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. On the contrary, other reports highlight a tumor-killing role of autophagy during cancer treatment. Herein, this review aims to revisit the key features of autophagy, summarize the seemingly contradictory roles of autophagy during both tumorigenesis and cancer chemotherapy, and evaluate the feasibility of altering the level of cellular autophagy as part of cancer adjuvant treatment.

Proteomics Identification of Annexin A2 as a Key Mediator in the Metastasis and Proangiogenesis of Endometrial Cells in Human Adenomyosis

Adenomyosis is a common estrogen-dependent disorder of females characterized by a downward extension of the endometrium into the uterine myometrium and neovascularization in ectopic lesions. It accounts for chronic pelvic pain, dysmenorrhea, menorrhagia, and infertility in 8.8–61.5% women worldwide. However, the molecular mechanisms for adenomyosis development remain poorly elucidated. Here, we utilized a two-dimensional polyacrylamide gel electrophoresis/MS-based proteomics analysis to compare and identify differentially expressed proteins in matched ectopic and eutopic endometrium of adenomyosis patients. A total of 93 significantly altered proteins were identified by tandem MS analysis. Further cluster analysis revealed a group of estrogen-responsive proteins as dysregulated in adenomyosis, among which annexin A2, a member of annexin family proteins, was found up-regulated most significantly in the ectopic endometrium of adenomyosis compared with its eutopic counterpart. Overexpression of ANXA2 was validated in ectopic lesions of human adenomyosis and was found to be tightly correlated with markers of epithelial to mesenchymal transition and dysmenorrhea severity of adenomyosis patients. Functional analysis demonstrated that estrogen could remarkably up-regulate ANXA2 and induce epithelial to mesenchymal transition in an in vitro adenomyosis model. Enforced expression of ANXA2 could mediate phenotypic mesenchymal-like cellular changes, with structural and functional alterations in a β-catenin/T-cell factor (Tcf) signaling-associated manner, which could be reversed by inhibition of ANXA2 expression. We also proved that enforced expression of ANXA2 enhanced the proangiogenic capacity of adenomyotic endometrial cells through HIF-1α/VEGF-A pathway. In vivo, we demonstrated that ANXA2 inhibition abrogated endometrial tissue growth, metastasis, and angiogenesis in an adenomyosis nude mice model and significantly alleviated hyperalgesia. Taken together, our data unraveled a dual role for ANXA2 in the pathogenesis of human adenomyosis through conferring endometrial cells both metastatic potential and proangiogenic capacity, which could serve as a potential therapeutic target for the treatment of adenomyosis patients.

Preventing postoperative abdominal adhesions in a rat model with PEG-PCL-PEG hydrogel

Background Poly (ethylene glycol)-poly (ɛ-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG, PECE) hydrogel has been demonstrated to be biocompatible and thermosensitive. In this study, its potential efficacy and mechanisms of preventing postsurgical abdominal adhesions were investigated. Results PECE hydrogel was transformed into gel state from sol state in less than 20 seconds at 37°C. None of the animals treated with the hydrogel (n = 15) developed adhesions. In contrast, all untreated animals (n = 15) had adhesions that could only be separated by sharp dissection (P < 0.001). The hydrogel adhered to the peritoneal wounds, gradually disappeared from the wounds within 7 days, and transformed into viscous fluid, being completely absorbed within 12 days. The parietal and visceral peritoneum were remesothelialized in about 5 and 9 days, respectively. The hydrogel prevented the formation of fibrinous adhesion and the invasion of fibroblasts. Also, along with the hydrogel degradation, a temporary inflammatory cell barrier was formed which could effectively delay the invasion of fibroblasts during the critical period of mesothelial regeneration. Conclusion The results suggested that PECE hydrogel could effectively prevent postsurgical intra-abdominal adhesions, which possibly result from the prevention of the fibrinous adhesion formation and the fibroblast invasion, the promotion of the remesothelialization, and the hydroflotation effect.

Tumor microenvironment: The culprit for ovarian cancer metastasis?

Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently, with poor prognosis. However, the molecular mechanisms underlying ovarian cancer metastasis still remain unelucidated. The tumor microenvironment, consisting of stromal cells (including fibroblasts, macrophages, regulatory T cells, myeloid-derived suppressor cells, endothelial cells, pericytes and platelets), the extracellular matrix component (EMC) (including inflammatory cytokines, chemokines, matrix metalloproteinases, integrins, and other secreted molecules) and exosomes (small extracellular vesicles loaded with molecules), establishes an autocrine-paracrine communication circuit that reinforces invasion and cancer cell metastasis via reciprocal signaling. Recent evidences have unraveled the significant contribution of tumor microenvironment to ovarian cancer metastasis. In this review, we provide a comprehensive landscape of the reciprocity between tumor stroma and ovarian cancer cells upon metastasis, aiming to offer novel clues on the development of novel diagnostic biomarkers and therapeutic targets for ovarian cancer in future clinical practice.

Long non-coding RNA LINC00092 acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer

The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs in vitro and in vivo were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14-high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. Cancer Res; 77(6); 1369-82. ©2017 AACR.

Prevention of post-surgical abdominal adhesions by a novel biodegradable thermosensitive PECE hydrogel.

BackgroundPost-operative peritoneal adhesions are common and serious complications for modern medicine. We aim to prevent post-surgical adhesions using biodegradable and thermosensitive poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) hydrogel. In this work, we investigated the effect of PECE hydrogel on preventing post-surgical abdominal adhesions in mouse and rat models.ResultsThe PECE hydrogel in sol state could be transformed into gel in less than 20 s at 37°C. In addition, the PECE hydrogel could be easily adhered to the damaged peritoneal surfaces, and be gradually degraded and absorbed by the body within 14 days along with the healing of peritoneal wounds. A notable efficacy of the PECE hydrogel in preventing peritoneal adhesions was demonstrated in the animal models. In contrast, all untreated animals developed adhesions requiring sharp dissection. Furthermore, no significant histopathological changes were observed in main organs of the hydrogel-treated animals.ConclusionOur results suggested that the thermosensitive PECE hydrogel was an effective, safe, and convenient agent on preventing post-surgical intro-abdominal adhesions.

Hypoxia: The driving force of uterine myometrial stem cells differentiation into leiomyoma cells

We propose that stem cells that display specific phenotypic and functional characteristics exist in human uterine myometrium. Under hypoxic circumstances, estrogen signaling pathways in certain myometrial stem cells are aberrantly activated, which leads to continuous differentiation of this portion of cells into leiomyoma cells. This process also protects the cells from undergoing physiological apoptotic or dedifferentiation. Therefore, we summarized some evidences for our bases and hypothesize that hypoxia may be the key contributor to the pathogenesis of leiomyoma through aberrant estrogen pathway activation of myometrial stem cells.

Anti-tumor activity of N-trimethyl chitosan-encapsulated camptothecin in a mouse melanoma model

BackgroundCamptothecin (CPT) has recently attracted increasing attention as a promising anticancer agent for a variety of tumors. But the clinical application is largely hampered by its extreme water insolubility and unpredictable side effect. It is essential to establish an efficient and safe protocol for the administration of CPT versus melanoma.MethodsCamptothecin was encapsulated with N-trimethyl chitosan (CPT-TMC) through microprecipitation and sonication. Its inhibition effect on B16-F10 cell proliferation and induction of apoptosis was evaluated by MTT assay and flow cytometric analysis in vitro. The anti-tumor activity of CPT-TMC was evaluated in C57BL/6 mice bearing B16-F10 melanoma. Tumor volume, tumor weight and survival time were recorded. Assessment of apoptotic cells within tumor tissue was performed by TUNEL assay. Antiangiogenesis and antiproliferation effects of CPT-TMC in vivo were conducted via CD31 and PCNA immunohistochemistry, respectively.ResultsCPT-TMC efficiently inhibited B16-F10 cells proliferation and increased apoptosis in vitro. Experiment group showed significant inhibition compared with free CPT-treated group (81.3% vs. 56.9%) in the growth of B16-F10 melanoma xenografts and prolonged the survival time of the treated mice (P < 0.05). Decreased cell proliferation, increased tumor apoptosis as well as a reduction in angiogenesis were observed.ConclusionsOur data suggest that N-trimethyl chitosan-encapsulated camptothecin is superior to free CPT by overcoming its insolubility and finally raises the potential of its application in melanoma therapy.

Comprehensive proteomic analysis of host cell lipid rafts modified by HBV infection

Lipid rafts are cholesterol- and sphingolipid-rich membrane microdomains that have been shown to participate in the entry, assembly and budding of various viruses. However, their involvement in HBV replication remains poorly characterized. In a preliminary study, we observed that HBV release could be markedly impaired by methyl-β-cyclodextrin mediated depletion of cholesterol in lipid rafts, and that this effect could be reversed by replenishment of exogenous cholesterol, suggesting that lipid rafts play an important role in the HBV life cycle. To further understanding how HBV exploited host cell lipid rafts to benefit replication, comprehensive proteomic approaches were used to profile the proteome changes of host cell lipid rafts in response to HBV infection using 2DE-MS/MS, in combination with SILAC-based quantitative proteomics. Using these approaches, a total of 97 differentially expressed proteins were identified. Bioinformatics analysis suggested that multiple host cell pathways were involved in the HBV infection processes including signal transduction, metabolism, immune response, transport, vesicle trafficking, cell adhesion and cellular ion homeostasis. These data will provide valuable clues for further investigation of HBV pathogenesis.

The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer

HSulf-1 (heparan sulfate 6-O-endosulfatase 1), a commonly downregulated gene in the majority of ovarian cancer cell lines, has been identified to play an important role in regulating tumorigenesis. Our previous studies demonstrated that HSulf-1 could inhibit angiogenesis and tumorigenesis in vivo. The employment of polymeric nanoparticles to deliver functional gene holds much promise as an effective therapeutic strategy against ovarian cancer. To develop more effective therapy, in this study, we investigated the antitumor effect of heparin-polyethyleneimine (HPEI) nanogels delivering HSulf-1 combined with cisplatin (DDP) on ovarian cancer. Expression of HSulf-1 in vitro and in vivo was determined by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. A SKOV3 intraperitoneal ovarian carcinomatosis model in nude mice was established to assess the antitumor efficacy. Mice were treated with NS, pEP/HPEI complexes, pHSulf-1/HPEI complexes, DDP or pHSulf-1/HPEI plus DDP, respectively. Intraperitoneal tumors were weighed. Antiangiogenic effect in vivo was evaluated by CD31 immunostaining and alginate-encapsulate tumor cell assay. Detection of the proliferative cells and apoptotic cells in tumor tissues were performed by Ki-67 staining and TUNEL assay. Stable expression of HSulf-1 was detected in the pHSulf-1/HPEI and pHSulf-1/HPEI plus DDP groups. The combination of pHSulf-1/HPEI complexes with DDP exhibited enhanced antitumor activity, compared with the monotherapy of HSulf-1 or DDP alone (P<0.01). the combination therapy exerted significant antitumor activity through enhanced antiangiogenesis, induction of apoptosis and suppression of cell proliferation. Collectively, these observations provide evidence that HPEI nanogels delivering HSulf-1 combined with DDP may have a promising application in the therapy of human ovarian cancer.