Hongyan Zhu
University of Chicago
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Featured researches published by Hongyan Zhu.
Inflammatory Bowel Diseases | 2012
Joel Pekow; Urszula Dougherty; Reba Mustafi; Hongyan Zhu; Masha Kocherginsky; David T. Rubin; Stephen B. Hanauer; John Hart; Eugene B. Chang; Alessandro Fichera; Loren Joseph; Marc Bissonnette
Background: miR‐143 and miR‐145 are believed to function as colon cancer tumor suppressors, as they inhibit colon cancer cell growth and are downregulated in sporadic colonic tumors. We speculated that miR‐143 and miR‐145 might also be downregulated and contribute to malignant transformation of colonic epithelium in longstanding ulcerative colitis (UC). Methods: Biopsies were obtained 20 cm proximal to the anus from individuals with quiescent UC and from normal controls. RNA and proteins were extracted and measured. miR‐143 and miR‐145 were quantified by real‐time polymerase chain reaction (PCR) and miR‐145 was also assessed by in situ hybridization. Putative targets of these miRNAs, K‐RAS, API5, MEK‐2 (miR‐143), and IRS‐1 (miR‐145) were determined by western blotting. To assess the effects of miR‐143 and miR‐145 on these predicted targets, HCT116 and HCA‐7 colorectal cancer cells were transfected with miR‐143 and miR‐145 and expression levels of these proteins were measured. Results: In UC, miR‐143 and miR‐145 were significantly downregulated 8.3‐fold (3.4–20.1) (P < 0.0001) and 4.3‐fold (2.3–7.8) (P < 0.0001), respectively, compared to normal colon. In contrast, IRS‐1, K‐RAS, API5, and MEK‐2 were upregulated in UC, consistent with their assignments as targets of these miRNAs. Furthermore, transfected miR‐143 and miR‐145 significantly downregulated these proteins in HCT116 or HCA‐7 cells. Conclusions: Compared to normal colonic mucosa, in chronic UC miR‐143 and miR‐145 were significantly downregulated and their predicted targets, IRS‐1, K‐RAS, API5, and MEK‐2 were upregulated. We postulate that loss of these tumor suppressor miRNAs predispose to chronic inflammation and neoplastic progression in IBD. (Inflamm Bowel Dis 2011;)
Cancer Research | 2006
Ezra E.W. Cohen; Mark W. Lingen; Bangmin Zhu; Hongyan Zhu; Michael W. Straza; Carolyn Pierce; Leslie E. Martin; Marsha Rich Rosner
Protein kinase C (PKC) zeta has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCzeta is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCzeta expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCzeta expression from normal to malignant tissue. PKCzeta activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCzeta using either kinase-dead PKCzeta mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCzeta inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCzeta is associated with SCCHN progression, (b) PKCzeta mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCzeta mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCzeta inhibitors function additively with other inhibitors that target similar or complementary signaling pathways.
Cancer Research | 2009
Ezra E.W. Cohen; Hongyan Zhu; Mark W. Lingen; Leslie E. Martin; Wen Liang Kuo; Eugene A. Choi; Masha Kocherginsky; Joel S. Parker; Christine H. Chung; Marsha Rich Rosner
Protein kinase Calpha (PKCalpha) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKCalpha promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKCalpha inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCalpha inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKCalpha down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKCalpha and cyclin E protein expression are increased in primary tumors, and PKCalpha inversely correlates with miR-15a expression in primary tumors. Finally, PKCalpha is associated with poor prognosis in SCCHN. These results identify PKCalpha as a key regulator of SCCHN tumor cell growth by a mechanism involving activation of mitogen-activated protein kinase, an initiator of the cell cycle, and suppression of miR-15a, an inhibitor of DNA synthesis. Although the specific components may be different, this type of feed-forward loop network, consisting of a stimulus that activates a positive signal and removes a negative brake, is likely to be a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli.
Clinical Cancer Research | 2009
Urszula Dougherty; Dario Cerasi; Ieva Taylor; Masha Kocherginsky; Ummuhan Tekin; Shamiram Badal; Lata M. Aluri; Amikar Sehdev; Sonia R. Cerda; Reba Mustafi; Jorge Delgado; Loren Joseph; Hongyan Zhu; John Hart; David W. Threadgill; Alessandro Fichera; Marc Bissonnette
Purpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined. Experimental Design: A/J C57BL6/J mice with wild-type Egfr (Egfrwt) or loss-of-function waved-2 Egfr (Egfrwa2) received azoxymethane followed by standard (5 fat) or western-style (20 fat) diet. As F1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and real-time PCR. Results:Egfrwt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfrwa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2 versus 36.7; P < 0.05) and cancer incidence (43.9 versus 16.7; P < 0.05) only in Egfrwt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfrwt mice. In tumors, dietary fat and Egfrwt upregulated transforming growth factor-, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfrwt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor- in normal colon. Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):67809)
Carcinogenesis | 2012
Reba Mustafi; Urszula Dougherty; Hardik B. Shah; Hooman Dehghan; Ariel Gliksberg; Jiang Wu; Hongyan Zhu; Loren Joseph; John Hart; Caroline Dive; Alessandro Fichera; David W. Threadgill; Marc Bissonnette
Colon cancer growth requires growth-promoting interactions between malignant colonocytes and stromal cells. Epidermal growth factor receptors (EGFR) are expressed on colonocytes and many stromal cells. Furthermore, EGFR is required for efficient tumorigenesis in experimental colon cancer models. To dissect the cell-specific role of EGFR, we manipulated receptor function on stromal cells and cancer cells. To assess the role of stromal EGFR, HCT116 human colon cancer cells were implanted into immunodeficient mice expressing dominant negative (DN) Egfr(Velvet/+) or Egfr(+/+). To assess the role of cancer cell EGFR, HCT116 transfectants expressing inducible DN-Egfr were implanted into immunodeficient mice. To dissect EGFR signals in vitro, we examined colon cancer cells in monoculture or in cocultures with fibroblasts for EGFR transactivation and prostaglandin synthase 2 (PTGS2) induction. EGFR signals were determined by blotting, immunostaining and real-time PCR. Tumor xenografts in Egfr(Velvet/+) mice were significantly smaller than tumors in Egfr(+/+) mice, with decreased proliferation (Ki67) and increased apoptosis (cleaved caspase-3) in cancer cells and decreased stromal blood vessels. Mouse stromal transforming growth factor alpha (TGFA), amphiregulin (AREG), PTGS2 and Il1b and interleukin-1 receptor 1 (Il1r1) transcripts and cancer cell beta catenin (CTNNB1) and cyclin D1 (CCND1) were significantly lower in tumors obtained from Egfr(Velvet/+) mice. DN-EGFR HCT116 transfectants also formed significantly smaller tumors with reduced mouse Areg, Ptgs2, Il1b and Il1r1 transcripts. Coculture increased Caco-2 phospho-active ERBB (pERBB2), whereas DN-EGFR in Caco-2 cells suppressed fibroblast PTGS2 and prostaglandin E2 (PGE2). In monoculture, interleukin 1 beta (IL1B) transactivated EGFR in HCT116 cells. Stromal cell and colonocyte EGFRs are required for robust EGFR signals and efficient tumor growth, which involve EGFR-interleukin-1 crosstalk.
Gastroenterology | 2010
Hongyan Zhu; Urszula Dougherty; Reba Mustafi; Victoria L. Robinson; Joel Pekow; Alessandro Fichera; Loren Joseph; Marc Bissonnette
Background and Aims: microRNAs (miRNAs) are involved in the pathogenesis of multiple human cancers, including CRC. Dysregulation of global miRNA profiles, which often associates with loss of expression of certain miRNAs, is a common feature in CRC. Whereas CpG island hypermethylation has been proposed to be a potential mechanism for miRNA silencing, this field remains largely unexplored. In this study, we describe the epigenetic regulation of miR-137 and its contribution to colorectal carcinogenesis. Methods: We determined the methylation status of the miR-137 CpG island in a panel of six CRC cell lines and 409 colorectal tissues (21 normal colonic mucosae from healthy individuals (N-N), 160 primary CRC tissues with corresponding adjacent normal colonic mucosa (N-C) and 68 colonic adenomas) by bisulfite pyrosequencing. TaqMan RT-PCR and in situ hybridization (ISH) were used to analyze miR-137 expression. In Vitro functional analysis of miR-137 was performed using precursor-miRNA transfection. Downstream genetic targets of miR-137 were identified by gene expression microarray analysis in combination with in silico predictions. Western blotting and luciferase assays were performed to validate the miRNA:mRNA interactions. Results: Methylation of the miR-137 CpG island was frequent in CRC cell lines (100%), adenomas (82.3%) and CRCs (81.4%) but not in N-C (14.4%; p<0.0001 for CRC) and N-N (4.7%; p<0.0001 for CRC). When compared to miR-137 unmethylated tumors, methylated CRCs were more frequently associated with KRAS mutations (37% vs 14%; p= 0.046) and older age (66 vs 60 years; p= 0.024). ISH results revealed that miR-137 expression was restricted to the colonocytes in normal mucosa, and was absent in CRC tissues. TaqMan RT-PCR analysis showed an inverse correlation between methylation and expression both in CRC tissues and cell lines. Transfection of the miR-137 precursor into CRC cell lines significantly decreased the cell proliferation index (p=0.0029). Functional assays validated an interaction between miR-137 and LSD-1, which plays a crucial role in the maintenance of DNAmethylation.Conclusions: Our data suggest that miR-137 acts as a tumor suppressor in the colon, and is frequently silenced by promoter hypermethylation. Frequent methylation found in adenomatous polyps suggests it is an early event in colorectal carcinogenesis. The interaction between miR-137 and LSD-1 suggests a mechanistic explanation for these observations and highlights the potential significance of this tumor-suppressive miRNA in epigenetic processes in colorectal tumorigenesis.
Gastroenterology | 2010
Joel Pekow; Urszula Dougherty; Hongyan Zhu; Victoria L. Robinson; Reba Mustafi; Nanda Venu; Karen E. Kim; Loren Joseph; Alessandro Fichera; Marc Bissonnette
G A A b st ra ct s at the enhancer in Pargyline-treated cells. These results suggest that H3K9Me or H3K9Me2specific demethylase activity of LSD1 at the secretin enhancer with acetylation of H3K9 is prerequisite for transcriptional activation by NeuroD. We conclude that LSD1 and CtBP, in the context of the secretin gene, engage specific chromatin-modifying activities to function as coactivator rather than a corepressor. Demethylation may represent one such activity that removes the repressive mark, H3K9Me2 to maintain expression of the secretin gene. Our observations illustrate the increasingly recognized importance of chromatin structure and the histone code in regulation of gene transcription.
Gastroenterology | 2009
Hongyan Zhu; Urszula Dougherty; Loren Joseph; Victoria L. Robinson; Jiang Wu; Zhiqun Song; Reba Mustafi; Alessandro Fichera; Marc Bissonnette
Inflammatory Bowel Diseases | 2011
Joel Pekow; Urszula Dougherty; Hongyan Zhu; David T. Rubin; S Hanauer; Russell D. Cohen; Eugene B. Chang; Alessandro Fichera; Marc Bissonnette
Inflammatory Bowel Diseases | 2011
Joel Pekow; Urszula Dougherty; Hongyan Zhu; David T. Rubin; S Hanauer; Russell D. Cohen; Alessandro Fichera; Eugene B. Chang; Marc Bissonnette