Kin Lam Ellis Fok

Publications (22) View all

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  Available from: Hao Chen

  Article: New insights into germ cell migration and survival/apoptosis in spermatogenesis: Lessons from CD147.

  Hao Chen, Kin Lam Fok, Xiaohua Jiang, Hsiao Chang Chan
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  ABSTRACT: CD147, also named basigin (Bsg) or extracellular matrix (ECM) metalloproteinase inducer (EMMPRIN), is a highly glycosylated protein first identified as a tumor cell surface molecule. In cancer, it is well established that CD147 promotes metastasis by stimulating the production of MMPs. Recent studies have also suggested that it may be associated with tumor growth and angiogenesis. Interestingly, CD147 is expressed in germ cells of different development stages in the testis and its knockout mice are infertile, indicating an essential role of CD147 in spermatogenesis. While the detailed involvement of CD147 in spermatogenesis remains elusive, our recent findings have revealed a dual role of CD147 in germ cell development. On the one hand, it regulates the migration of spermatogonia and spermatocytes via the induction of MMP-2 production; on the other hand, it specifically regulates the survival/apoptosis of spermatocytes but not spermatogonia through a p53-independent pathway. In this review, we aim to provide an overview on the functions of CD147, comparing its roles in cancer and the testis, thereby providing new insights into the regulatory mechanisms underlying the process of spermatogenesis.
  Spermatogenesis. 10/2012; 2(4):264-272.
• Article: Cryptorchidism-induced CFTR down-regulation results in disruption of testicular tight junctions through up-regulation of NF-κB/COX-2/PGE2.

  Jing Chen, Kin Lam Fok, Hui Chen, Xiao Hu Zhang, Wen Ming Xu, Hsiao Chang Chan
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  ABSTRACT: Does elevated temperature-induced cystic fibrosis transmembrane conductance regulator (CFTR) down-regulation in Sertoli cells in cryptorchid testis disrupt testicular tight junctions (TJs) through the nuclear factor kappa B (NF-κB)/cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)) pathway? SUMMARY ANSWER: Our results suggest that CFTR may be involved in regulating testicular TJs and the blood-testis barrier (BTB) through its negative regulation of the NF-κB/COX-2/PGE(2) pathway in Sertoli cells, a defect of which may result in the spermatogenesis defect in cryptorchidism. WHAT IS KNOWN ALREADY: Cryptorchidism, or undescended testes, is known to result in defective spermatogenesis. Although an elevated testicular temperature is regarded as an important factor affecting spermatogenesis in cryptorchidism, the exact mechanism remains elusive. It is known that the expression of functional CFTR is temperature sensitive. Our previous study has demonstrated that CFTR negatively regulates NF-κB/COX-2/PGE(2) in bronchial epithelial cells. Disruption of TJs by COX-2/PGE(2) has been found in tumour cells. Expression of CFTR, NF-κB, COX-2 and TJ proteins was examined in the testes of a surgical-induced cryptorchidism mouse model and a testicular hyperthermia mouse model, as well as in control or CFTR-inhibited/knocked down primary rat Sertoli cells. PGE(2) production was measured by ELISA. Sertoli cell barrier function was determined by transepethelial resistance (TER) measurements in rat Sertoli cell primary cultures. BTB integrity in the cryptorchidism model was monitored by examining tracker dye injected into seminiferous tubules. Down-regulation of CFTR accompanied by activation of NF-κB, up-regulation of COX-2 and down-regulation of TJ proteins, including ZO-1 and occludin, was observed in a cryptorchidism mouse model. BTB leakage revealed impaired BTB integrity in cryptorchid testes, confirming the destruction of TJs. The inverse correlation of CFTR and COX-2 was further confirmed in a mouse testis hyperthermia model and CFTR knockout mouse model. Culturing primary Sertoli cells at 37°C, which mimics the pathological condition of cryptorchidism, led to a significant decrease in CFTR and increase in COX-2 expression and PGE(2) production compared with the culture at the physiological 32°C. Inhibition or knockdown of CFTR led to increased COX-2 but decreased ZO-1 and occludin expression in Sertoli cells, which could be mimicked by PGE(2), but reversed by NF-κB or COX-2 inhibitor, suggesting that the regulation of TJs by CFTR is mediated by a NF-κB/COX-2/PGE(2) pathway. Inhibition of CFTR or administration of PGE(2) significantly decreased Sertoli cell TER. This study has tested only the CFTR/NF-κB/COX-2/PGE(2) pathway in mouse testes in vivo and in rat Sertoli cells in vitro, and thus, it has some limitations. Further investigations in other species, especially humans, are needed. WIDER IMPLICATIONS OF THE FINDINGS: Our study may shed more light on one of the aspects of the complicated underlying mechanisms of defective spermatogenesis induced by cryptorchidism.
  Human Reproduction 07/2012; 27(9):2585-97. · 4.47 Impact Factor
• Article: Activation of the epithelial Na+ channel triggers prostaglandin E₂ release and production required for embryo implantation.

  Ye Chun Ruan, Jing Hui Guo, Xinmei Liu, Runju Zhang, Lai Ling Tsang, Jian Da Dong, Hui Chen, Mei Kuen Yu, Xiaohua Jiang, Xiao Hu Zhang, Kin Lam Fok, Yiu Wa Chung, Hefeng Huang, Wen Liang Zhou, Hsiao Chang Chan
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  ABSTRACT: Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na⁺ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca²⁺ influx that leads to prostaglandin E₂ (PGE₂) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE₂ production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.
  Nature medicine 06/2012; 18(7):1112-7. · 27.14 Impact Factor
• Article: CFTR mediates bicarbonate-dependent activation of miR-125b in preimplantation embryo development.

  Yong Chao Lu, Hui Chen, Kin Lam Fok, Lai Ling Tsang, Mei Kuen Yu, Xiao Hu Zhang, Jing Chen, Xiaohua Jiang, Yiu Wa Chung, Alvin Chun Hang Ma, Anskar Yu Hung Leung, He Feng Huang, Hsiao Chang Chan
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  ABSTRACT: Although HCO(3)(-) is known to be required for early embryo development, its exact role remains elusive. Here we report that HCO(3)(-) acts as an environmental cue in regulating miR-125b expression through CFTR-mediated influx during preimplantation embryo development. The results show that the effect of HCO(3)(-) on preimplantation embryo development can be suppressed by interfering the function of a HCO(3)(-)-conducting channel, CFTR, by a specific inhibitor or gene knockout. Removal of extracellular HCO(3)(-) or inhibition of CFTR reduces miR-125b expression in 2 cell-stage mouse embryos. Knockdown of miR-125b mimics the effect of HCO(3)(-) removal and CFTR inhibition, while injection of miR-125b precursor reverses it. Downregulation of miR-125b upregulates p53 cascade in both human and mouse embryos. The activation of miR-125b is shown to be mediated by sAC/PKA-dependent nuclear shuttling of NF-κB. These results have revealed a critical role of CFTR in signal transduction linking the environmental HCO(3)(-) to activation of miR-125b during preimplantation embryo development and indicated the importance of ion channels in regulation of miRNAs.
  Cell Research 06/2012; 22(10):1453-1466. · 8.19 Impact Factor
• Article: Regulation of apoptosis by Bat3-enhanced YWK-II protein/APLP2 stability.

  Wei Wu, Wei Song, Shuchun Li, Songying Ouyang, Kin Lam Fok, Ruiying Diao, Shiying Miao, Hsiao Chang Chan, Linfang Wang
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  ABSTRACT: YWK-II protein/APLP2 is a member of an evolutionarily conserved protein family that includes amyloid precursor protein (APP) and amyloid precursor like protein-1 (APLP1). We have previously demonstrated that YWK-II/APLP2 functions as a novel G(0)-protein-coupled receptor for Müllerian inhibiting substance (MIS) in cell survival. However, factors regulating the stability and turnover of YWK-II/APLP2 have not been identified. Here we present evidence that human leukocyte antigen-B-associated transcript 3 (Bat3), an important regulator involved in apoptosis, can interact with YWK-II/APLP2 and enhance its stability by reducing its ubiquitination and degradation by the ubiquitin-proteasome system. Co-expression of different Bat3 domain deletion constructs with YWK-II/APLP2 reveals that the proline-rich domain of Bat3 is required for its binding to YWK-II/APLP2. In addition, we find that the protein levels of YWK-II/APLP2 could be enhanced by nuclear export of Bat3 under apoptotic stimulation. We also find elevated levels of Bat3 and YWK-II/APLP2 in human colorectal cancer with a positive correlation between the two. Taken together, these results have revealed a previously undefined mechanism regulating cell apoptosis and suggest that aberrant enhancement of YWK-II/APLP2 by nuclear export of Bat3 may play a role in cancer development by inhibiting cell apoptosis.
  Journal of Cell Science 05/2012; · 6.11 Impact Factor