Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression

Hypoxia has been recognized as one of the fundamentally important features of solid tumors and plays a critical role in various cellular and physiologic events, including cell proliferation, survival, angiogenesis, immunosurveillance, metabolism, as well as tumor invasion and metastasis. These responses to hypoxia are at least partially orchestrated by activation of the hypoxia-inducible factors (HIFs). HIF-1 is a key regulator of the response of mammalian cells to oxygen deprivation and plays critical roles in the adaptation of tumor cells to a hypoxic microenvironment. Hypoxia and overexpression of HIF-1 have been associated with radiation therapy and chemotherapy resistance, an increased risk of invasion and metastasis, and a poor clinical prognosis of solid tumors. The discovery of HIF-1 signaling has led to a rapidly increasing understanding of the complex mechanisms involved in tumor hypoxia and has helped greatly in screening novel anticancer agents. In this review, we will first introduce the cellular responses to hypoxia and HIF-1 signaling pathway in hypoxia, and then summarize the multifaceted role of hypoxia in the hallmarks of human cancers.

Role of hypoxia in the hallmarks of human cancer.

The complex cross-talk of intricate intercellular signaling networks between the tumor and stromal cells promotes cancer progression. Hypoxia is one of the most common conditions encountered within the tumor microenvironment that drives tumorigenesis. Most responses to hypoxia are elicited by a family of transcription factors called hypoxia-inducible factors (HIFs), which induce expression of a diverse set of genes that assist cells to adapt to hypoxic environments. Among the three HIF protein family members, the role of HIF-1 is well established in cancer progression. HIF-1 functions as a signaling hub to coordinate the activities of many transcription factors and signaling molecules that impact tumorigenesis. This mini review discusses the complex role of HIF-1 and its context-dependent partners under various cancer-promoting events including inflammation and generation of cancer stem cells, which are implicated in tumor metastasis and relapse. In addition, the review highlights the importance of therapeutic targeting of HIF-1 for cancer prevention.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.29519

HIF-1 at the crossroads of hypoxia, inflammation, and cancer.

It is now recognized that the host microenvironment undergoes extensive change during the evolution and progression of cancer. This involves the generation of cancer-associated fibroblasts (CAFs), which, through release of growth factors and cytokines, lead to enhanced angiogenesis, increased tumour growth and invasion. It has also been demonstrated that CAFs may modulate the cancer stem cell (CSC) phenotype, which has therapeutic implications. The altered fibroblast phenotype also contributes to the development of an altered extracellular matrix (ECM), with synthesis of ECM isoforms rarely found in normal tissues, including tenascin-C isoforms and the fibronectin EDA isoform. There is also emerging evidence of how the tensile strength of the tumour-associated ECM may be modified and lead to altered signalling in tumour cells. The hypoxic environment of the tumour stimulates angiogenesis and also impacts on other aspects of cell signalling, including the c-met pathway and lysyl oxidase-mediated signalling, which can directly promote tumour cell invasion. The inflammatory infiltrate associated with many solid tumours also modulates tumour function, having both anti- and pro-tumour effects. All of these components of the microenvironment provide potential targets for therapeutic attack, with a number of molecules already in clinical trials. It is also becoming evident that characterizing the tumour microenvironment can provide important prognostic and predictive information about tumours, independent of the tumour cell phenotype.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.2803

Jekyll and Hyde: the role of the microenvironment on the progression of cancer.

Epithelial-Mesenchymal Transition in Cancer: A Historical Overview

Objectives Epithelial-mesenchymal transition (EMT) is an important process in tumor development, and several studies suggest that the Wnt/beta-catenin signal pathway may play an important role in EMT. However, there is no direct evidence showing that the Wnt/beta-catenin pathway actually determines the EMT induced by an exogenous signal. Our previous research has successfully proved that overexpression of hypoxia-inducible factor-1alpha (HIF-1alpha) could induce EMT in LNCaP cells, but not in PC-3. The present study aims to determine whether the signal of HIF-1alpha for inducing prostate cancer cells to undergo EMT might possibly pass through the Wnt/beta-catenin pathway. Methods Epithelial-mesenchymal transition associated proteins were detected in several human prostate carcinoma cell lines by Western blot, and then we distinguished the EMT positive cell lines from the EMT negative cell lines. Furthermore, we evaluated the possible correlation between potency of invasiveness and proliferation among these cell lines with different characteristics of EMT using Matrigel transwell and thiazolyl blue tetrazolium bromide (MTT) assays. Finally, the different expression of some critical proteins and genes in Wnt/beta-catenin signaling pathway were analyzed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) in these cells with different characteristics of EMT. Results Among several prostate cancer cell lines, PC-3, LNCaP and PC-3/HIF-1alpha are EMT negative cell lines, whereas LNCaP/HIF-1alpha and IA8 have undergone the EMT process. EMT positive cells (LNCaP/HIF-1alpha and IA8) exhibit much stronger potency of invasiveness and proliferation than those of PC-3 and LNCaP, which belong to EMT negative cells. Interestingly, although PC-3/HIF-1alpha had not completed the EMT process, it still displayed stronger potency of invasion and proliferation, resembling EMT positive cells. The protein expression level of total glycogensynthase kinase 3beta (GSK-3beta) and phospho-GSK-3beta in LNCaP/HIF-1alpha, IA8 and PC-3/HIF-1alpha cells significantly decreased; however, the relative ratios of p-GSK3beta/t-GSK3beta in LNCaP/HIF-1alpha, IA8 and PC-3/HIF-1alpha cells were significantly higher than PC-3 and LNCaP. Consistently, beta-catenin protein expression increased in LNCaP/HIF-1alpha and IA8 cells, but not in PC-3/HIF-1alpha; RT-PCR confirmed these results, except for the enhanced transcription activity of beta-catenin mRNA in PC-3/HIF-1alpha. Conclusion Our data suggests that activation of the Wnt/beta-catenin signaling pathway correlates with the characteristic of EMT and potency of invasiveness and proliferation. This may be the critical factor that directly controls the process of EMT induced by HIF-1alpha in prostate cancer cells.

Role of Wnt/β‐catenin signaling pathway in epithelial‐mesenchymal transition of human prostate cancer induced by hypoxia‐inducible factor‐1α

BACKGROUND Environmental toxins can destroy the physiological process of spermatogenesis and even lead to male infertility. Resveratrol (RES) is a natural phytoalexin with a wide range of biological activities. Some recent researches have demonstrated that RES can increase sperm output and protect sperm from apoptosis caused by physical damage. However, there is no evidence indicating that it can also exhibit a similar activity in testis injury caused by environmental toxins. This study was designed to evaluate the protective effect of resveratrol on testis damaged by environmental toxins and to elucidate the possible mechanism of its protective effect. METHODS In this study 2, 5-hexanedione (2, 5-HD) was used as the injury agent. Forty male SD rats were randomly divided into 5 groups. During the first 5 weeks, group A was raised normally, groups B, C, D and E were exposed to 1% 2, 5-HD; during the following 9 weeks, group C, D, E received intragastric administration of different concentrations of resveratrol (20 mg x kg(-1) x d(-1), 40 mg x kg(-1) x d(-1) and 80 mg x kg(-1) x d(-1)), while groups A and B were treated by carboxymethylcellulose. Physical signs, body weight gain and testis weight were comparatively observed. Numbers and diameters of seminiferous tubules were analyzed following HE staining. In addition, expression of the c-kit protein and gene in spermatogenic cells in every group was detected with immunohistochemistry, Western blot or RT-PCR. RESULTS The 2, 5-HD treatment resulted in physical signs that became worse and in emarciated testis. HE staining and immunohistochemistry showed that seminiferous tubules became emarcid, obsolete spermatogonia being stagnant and expression of c-kit protein being depressed. After oral administration of resveratrol, the 2, 5-HD-induced physical signs were improved and close to the normal rats. The gain of body weight increased (P < 0.01). The recovery of testis weight was significant (P < 0.01). At the histological level, the seminiferous epithelia began to differentiate (P < 0.01); and even the physiological process of spermatogenesis restarted. Moreover, expression of c-kit protein and gene function resumed, although its expression remained different from the normal group. The diameter of and number of seminiferous tubules and the expression level of c-kit protein and gene activity were much closer to the normal group with increased doses of the resveratrol through oral administration. CONCLUSIONS Resveratrol could ameliorate markedly the dyszoospermia induced by 2, 5-HD and induce spermatogenesis. The expression of c-kit, which is a specific marker protein of spermatogenic cell membranes, could be regulated by resveratrol.

Resveratrol reestablishes spermatogenesis after testicular injury in rats caused by 2, 5-hexanedione.

OBJECTIVE To observe the expressions of E-cadherin and beta-catenin in LNCaP and ARCaP cell lines and explore their relationship with the metastasis of human prostate cancer METHODS The expressions and distribution of E-cadherin and beta-catenin in LNCaP and ARCaP cell lines (IF11 and IA8) were detected by Western blot and immunofluorescent staining RESULTS The expression of E-cadherin was high in LNCaP, but absent in IF11 and IA8, while beta-catenin was expressed highly in IF11 and LA8, but lowly in LNCaP Immunofluorescent staining showed that E-cadherin was mainly in the membrane of LNCaP, while beta-catenin both in the membrane of LNCaP and in the nuclei of IF11 and IA8 CONCLUSION E-cadherin and beta-catenin are differently expressed and distributed in prostate cancer cell lines with different characteristics of epithelial-mesenchymal transition (EMT), and the abnormal activation of the beta-catenin signal pathway may be involved in the EMT of prostate cancer cells

[Expressions of E-cadherin and beta-catenin in LNCaP and ARCaP cell lines and their significance].

Objective:To study the effect of finasteride on benign prostatic hyperplasia (BPH) related gross hematuria in patients receiving anticoagulant Methods: A total of 105 patients with BPH related gross hematuria were divided into an anticoagulant group (n = 81), treated with combined therapy of anticoagulants and finasteride, and a control group (n = 24), given finasteride only at 5 mg daily The therapeutic effects were compared by a 6-month follow-up Results: In the anticoagulant group, gross hematuria was cured in 52 patients (642%), taking an average time of 39 weeks (1-6 weeks), and improved in 12 patients (148%), as compared with 16 patients cured (667%), 32 weeks taken (1-5 weeks), and 4 patients improved (167%) in the control group The mean time taken to resolve hematuria was longer in the former (P 005) But the cure rates had no significant differences either between the two groups or among the subgroups receiving different anticoagulants Conclusion: Finasteride is an effective therapeutic for BPH related hematuria in patients receiving different anticoagulants It makes no significant differences in cure and effectiveness rates between patients treated with and without anticoagulant, but takes an average of longer time to resolve hematuria in patients receiving anticoagulant

[Finasteride: an effective therapeutic for benign prostatic hyperplasia related gross hematuria in patients receiving anticoagulant].

OBJECTIVE To study the effect of resveratrol on spermatogenesis after 2,5-hexanedione(2,5-HD)-induced testicular injury. METHODS Forty male SD rats were randomly divided into 5 groups. Group A were normally raised and Group B, C, D and E exposed to 1% 2,5-HD for 5 weeks, followed by administration of resveratrol of different concentrations (20, 40 and 80 mg/[ kg x d], respectively) to Group C, D and E for 9 weeks. Then the rats were killed, their physical signs, body weight gain and testis weight were assessed, and immunohistochemistry and Western blot analysis used to investigate the numbers and diameters of seminiferous tubules and the expression of c-kit protein of spermatogenic cell membrane. RESULTS The rats exposed to 2,5-HD showed weak body, lax skin, dim color pattern, tardy body weight gain, and emaciated testis. Immunohistochemistry revealed emaciated seminiferous tubules, stagnant obsolete spermatogonia and negative expression of c-kit protein. After resveratrol administration, the 2,5-HD-induced physical signs were improved and close to normal. Compared with those of the 2,5-HD injured group, the body weight and testis weight of the resveratrol treated group increased obviously (P < 0.01); and the aliquots of the seminiferous epithelia began to differentiate and the spermatogenesis and expression of c-kit protein partly resumed (P < 0.01). With increasing dose of resveratrol, the diameters and numbers of seminiferous tubules (P < 0.01) and the expression levels of c-kit protein (P < 0.01) were gradually and significantly restored almost to normal. CONCLUSION Resveratrol could promote the recovery of spermatogenesis after 2,5-HD-induced testicular injury.

Tao Peng

Papers

Role of Wnt/β‐catenin signaling pathway in epithelial‐mesenchymal transition of human prostate cancer induced by hypoxia‐inducible factor‐1α

Resveratrol reestablishes spermatogenesis after testicular injury in rats caused by 2, 5-hexanedione.

[Expressions of E-cadherin and beta-catenin in LNCaP and ARCaP cell lines and their significance].

[Finasteride: an effective therapeutic for benign prostatic hyperplasia related gross hematuria in patients receiving anticoagulant].

[Resveratrol helps restore spermatogenesis after testis injury induced by 2,5-hexanedione].