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Dive into the research topics where Mohamed Kamel Hassan is active.

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Featured researches published by Mohamed Kamel Hassan.


BioMed Research International | 2014

Apoptosis and Molecular Targeting Therapy in Cancer

Mohamed Kamel Hassan; Hidemichi Watari; A H Abu-Almaaty; Yusuke Ohba; Noriaki Sakuragi

Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.


Oncogenesis | 2013

Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET

Takashi Mitamura; Hidemichi Watari; Lei Wang; Hiromi Kanno; Mohamed Kamel Hassan; Masaya Miyazaki; Y Katoh; Taichi Kimura; Mishie Tanino; Hiroshi Nishihara; Shinya Tanaka; Noriaki Sakuragi

Ovarian cancer is one of the most aggressive female reproductive tract tumors. Paclitaxel (PTX) is widely used for the treatment of ovarian cancer. However, ovarian cancers often acquire chemotherapeutic resistance to this agent. We investigated the mechanism of chemoresistance by analysis of microRNAs using the ovarian cancer cell line KFr13 and its PTX-resistant derivative (KFr13Tx). We found that miR-31 was downregulated in KFr13Tx cells, and that re-introduction of miR31 re-sensitized them to PTX both in vitro and in vivo. miR-31 was found to bind to the 3′-UTR of mRNA of MET, and the decrease in MET correlated to higher sensitivity to PTX. Furthermore, co-treatment of KFr13Tx cells with MET inhibitors sensitized the tumor cells to PTX both in vitro and in vivo. In addition, lower levels of miR31 and higher expression of MET in human ovarian cancer specimens were significantly correlated with PTX chemoresistance and poor prognosis. This study demonstrated miR31-dependent regulation of MET for chemoresistance of ovarian cancer, raising the possibility that combination therapy with a MET inhibitor and PTX will increase PTX efficacy.


Gynecologic Oncology | 2008

Clusterin expression predicts survival of invasive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy

Hidemichi Watari; Yoko Ohta; Mohamed Kamel Hassan; Ying Xiong; Shinya Tanaka; Noriaki Sakuragi

OBJECTIVES The aim of this study was to evaluate the prognostic significance of clusterin expression in invasive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. METHODS Invasive cervical cancer specimens were obtained from 52 patients who underwent radical hysterectomy and systematic lymphadenectomy at Hokkaido University Hospital from 1997 to 2004. The expression of clusterin protein was analyzed by immunohistochemical staining. Findings were evaluated in relation to several clinicopathological factors. Survival analyses were performed by the Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. RESULTS Clusterin protein was present in the cytoplasm of cervical cancer cells. The expression of clusterin protein in invasive cervical cancer tissues was not related to any clinicopathologic factors analyzed. Patients with positive clusterin expression showed significantly worse prognosis than those with negative clusterin expression (p=0.017). Multivariate analysis including clusterin expression revealed that clusterin expression (p=0.006) and the number of positive node groups (p=0.002) were independent prognostic factors for survival. Survival of patients with invasive cervical cancer could be stratified into three groups by combination of clusterin expression and number of positive node groups with an estimated 5-year survival rate of 100.0% for no or one positive node group irrespective of clusterin expression (group A), 78.7% for multiple node groups with negative clusterin expression (group B), and 14.3% for multiple node groups with positive clusterin expression (group C) (p=0.03 for group A vs. group B, p=0.004 for group B vs. group C, and p<0.0001 for group A vs. group C). CONCLUSIONS Clusterin expression and the number of positive node groups were independent prognostic factors for invasive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. Clusterin might be a new molecular marker to predict the survival of cervical cancer patients with multiple positive node groups.


Nature Neuroscience | 2017

C9orf72 expansion disrupts ATM-mediated chromosomal break repair

Callum Walker; Saul Herranz-Martin; Evangelia Karyka; Chunyan Liao; Katherine Lewis; Waheba Elsayed; Vera Lukashchuk; Shih-Chieh Chiang; Swagat Ray; Pádraig J. Mulcahy; Mateusz Jurga; Ioannis Tsagakis; Tommaso Iannitti; Jayanth S. Chandran; Ian Coldicott; Kurt J. De Vos; Mohamed Kamel Hassan; Adrian Higginbottom; Pamela J. Shaw; Guillaume M. Hautbergue; Mimoun Azzouz; Sherif F. El-Khamisy

Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA–RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability.


Journal of Experimental & Clinical Cancer Research | 2011

Clusterin is a potential molecular predictor for ovarian cancer patient's survival: targeting Clusterin improves response to paclitaxel

Mohamed Kamel Hassan; Hidemichi Watari; Yimin Han; Takashi Mitamura; Masayoshi Hosaka; Lei Wang; Shinya Tanaka; Noriaki Sakuragi

BackgroundClusterin is a cytoprotective chaperone protein involved in numerous physiological processes, carcinogenesis, tumor growth and tissue remodelling. The purpose of this study was to investigate whether clusterin (CLU), an antiapoptotic molecule, could be a potential predictor molecule for ovarian cancer and whether or not targeting this molecule can improve survival of ovarian cancer patients.MethodsClusterin expression was compared between ten primary and their recurrent tumors from same patients immunohistochemically. We analyzed prognostic significance of CLU expression in another 47 ovarian cancer tissue samples by immunohistochemistry. We used small interference RNA to knock down CLU in the chemo-resistant ovarian cancer cell lines. KF-TX and SKOV-3-TX, paclitaxel-resistant ovarian cancer cells, were established from parental KF and SKOV-3 chemo-sensitive cell lines, respectively. Either siRNA or second generation antisense oligodeoxynucleotide against CLU (OGX-011), which is currently evaluated in clinical phase II trials in other cancer s, was used to modulate sensitivity to paclitaxel (TX) in ovarian cancer cells in vitro. Cellular viability assay, FACS analysis and annexin V staining were used to evaluate the comparative effect of CLU knocking down in ovarian cancer cells.ResultsImmunohistochemical analysis of CLU expression in primary ovarian cancer tissue specimens and their recurrent counterparts from same patients demonstrated higher expression of CLU in the recurrent resistant tumors compared with their primary tumors. High expression of CLU by immunohistochemistry among 47 surgical tissue specimens of early-stage (stage I/II) ovarian cancer, who underwent complete cytoreduction as a primary surgery, significantly related to poor survival, while none of other clinicopathological factors analyzed were related to survival in this patient cohort. Secretory CLU (s-CLU; 60 KDa) expression was upregulated in TX-resistant ovarian cancer cells compared to parental cells. Transfection of siRNA or OGX-011 clearly reduced CLU expression. Cell viability assay, FACS analysis and annexin V staining demonstrated that targeting CLU expression by siRNA or OGX-011 sensitized ovarian cancer cells to TX.ConclusionWe conclude that CLU could be a potential molecular target to predict survival while targeting this s-CLU may improve survival of patients with ovarian cancer.


Gynecologic Oncology | 2009

Cyr61, a member of ccn (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family, predicts survival of patients with endometrial cancer of endometrioid subtype

Hidemichi Watari; Ying Xiong; Mohamed Kamel Hassan; Noriaki Sakuragi

OBJECTIVES It has been reported that expression of Cyr61 decreased in endometrial cancers and cancer cell lines compared with normal endometrium, and forced expression of Cyr61 could suppress the growth of human endometrial cancer cells. However, in another report, Cyr61 was immunostained in most of endometrial cancer tissues analyzed. Thus, the aim of this study was to examine the expression of Cyr61 in endometrial cancer and to correlate Cyr61 expression with cinicopathologic factors in a larger cohort. METHODS We used immunohistochemistry and RT-PCR to examine the expression of Cyr61 in 92 endometrial carcinomas of endometrioid subtype. We correlated the expression of Cyr61 with various clinicopathologic factors in patients with endometrioid adenocarcinoma. Survival analyses were performed by the Kaplan Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. RESULTS Cyr61 expression was high in 21 of 92 cases of endometrioid adenocarcinoma (22.8%). High expression of Cyr61 was related to poor survival of patients with endometrioid adenocarcinoma. Multivariate analysis including Cyr61 expression revealed that Cyr61 expression and positive lymph node metastasis (LNM) were independent prognostic factors for survival. Survival of patients with endometrioid adenocarcinoma could be stratified into three groups by combination of Cyr61 expression and positive LNM with an estimated 5-year survival rate of 96.5% for no LNM irrespective of Cyr61 expression (group A), 85.7% for positive LNM with low/moderate expression of Cyr61 (group B), and 0% for positive LNM with high expression of Cyr61 (group C)(p=0.18 for group A vs group B, p=0.008 for group B vs group C, and p<0.0001 for group A vs group C). CONCLUSIONS Cyr61 is highly expressed in some endometrial cancer of endometrioid subtype. Cyr61 expression and positive LNM were independent prognostic factors for patients with endometrioid adenocarcinoma. Cyr61 might be a new molecular marker to predict the prognosis of patients with endometrioid adenocarcinoma.


Molecular Cancer | 2014

microRNA 31 functions as an endometrial cancer oncogene by suppressing Hippo tumor suppressor pathway

Takashi Mitamura; Hidemichi Watari; Lei Wang; Hiromi Kanno; Makiko Kitagawa; Mohamed Kamel Hassan; Taichi Kimura; Mishie Tanino; Hiroshi Nishihara; Shinya Tanaka; Noriaki Sakuragi

BackgroundWe aimed to investigate whether MIR31 is an oncogene in human endometrial cancer and identify the target molecules associated with the malignant phenotype.MethodsWe investigated the growth potentials of MIR31-overexpressing HEC-50B cells in vitro and in vivo. In order to identify the target molecule of MIR31, a luciferase reporter assay was performed, and the corresponding downstream signaling pathway was examined using immunohistochemistry of human endometrial cancer tissues. We also investigated the MIR31 expression in 34 patients according to the postoperative risk of recurrence.ResultsThe overexpression of MIR31 significantly promoted anchorage-independent growth in vitro and significantly increased the tumor forming potential in vivo. MIR31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3’-UTR and consequently promoted the translocation of YAP1, a key molecule in the Hippo pathway, into the nucleus. Meanwhile, the nuclear localization of YAP1 increased the transcription of CCND1. Furthermore, the expression levels of MIR31 were significantly increased (10.7-fold) in the patients (n = 27) with a high risk of recurrence compared to that observed in the low-risk patients (n = 7), and this higher expression correlated with a poor survival.ConclusionsMIR31 functions as an oncogene in endometrial cancer by repressing the Hippo pathway. MIR31 is a potential new molecular marker for predicting the risk of recurrence and prognosis of endometrial cancer.


Pathology & Oncology Research | 2010

Clusterin Expression Inversely Correlates with Chemosensitivity and Predicts Poor Survival in Patients with Locally Advanced Cervical Cancer Treated with Cisplatin-Based Neoadjuvant Chemotherapy and Radical Hysterectomy

Hidemichi Watari; Tatsuya Kanuma; Yoko Ohta; Mohamed Kamel Hassan; Takashi Mitamura; Masayoshi Hosaka; Takashi Minegishi; Noriaki Sakuragi

Overexpression of clusterin, an antiapoptotic molecule, has been reported to induce resistance to chemotherapy in a variety of cancer cell types. The aim of this study was to evaluate the significance of clusterin expression to predict response to platinum-based neoadjuvant chemotherapy and survival of patients with invasive cervical cancer who subsequently underwent radical hysterectomy. Biopsy specimens of invasive cervical cancer before neoadjuvant chemotherapy were obtained from 46 patients who subsequently underwent radical hysterectomy at Hokkaido University Hospital and Gunma University Hospital from 1994 to 2007. The expression of clusterin protein was analyzed by immunohistochemistry. Findings were evaluated in relation to several clinicopathological factors. Survival analyses were performed by the Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. Clusterin protein was mainly present in the cytoplasm of cervical cancer cells. The expression of clusterin protein in cervical cancer tissues before neoadjuvant chemotherapy was significantly related to poor response to chemotherapy among factors analyzed. Univariate analysis on prognostic factors showed that response to chemotherapy (p = 0.01), lymph node metastasis (p = 0.02), and clusterin expression (p = 0.02) were related to survival. Multivariate analysis revealed that lymph node metastasis (p = 0.03), and clusterin expression (p = 0.03) were independent prognostic factors for survival of cervical cancer patients. We conclude that clusterin expression could be a new molecular marker to predict response to platinum-based chemotherapy and survival of patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy.


Tumor Biology | 2011

Intracellular clusterin negatively regulates ovarian chemoresistance: compromised expression sensitizes ovarian cancer cells to paclitaxel

Mohamed Kamel Hassan; Hidemichi Watari; Lane K. Christenson; Saverio Bettuzzi; Noriaki Sakuragi

Understanding the molecular events that lead to paclitaxel (TX) resistance is necessary to identify effective means to prevent chemoresistance. Previously, results from our lab revealed that secretory clusterin (CLU) form positively mediates TX response in ovarian cancer cells. Thus, we had interest to study the role of another non-secreted form (intracellular clusterin (i-CLU)) in chemo-response. Here, we provide evidences that i-CLU form localizes mainly in the nucleus and differentially expressed in the TX-responsive KF cells, versus TX-resistant, KF-TX, ovarian cancer cells and negatively regulate cellular chemo-response. I-CLU was cloned, by deleting the secretion-leading signaling peptide from full-length CLU cDNA, and transiently over-expressed in OVK-18 cells. Forced expression of truncated i-CLU was mainly detectable in the nuclei and significantly reduced cellular growth, accumulating cells in G1 phase which finally died through apoptosis. Importantly, compromised expression of i-CLU under an inducible promoter was tolerated and did not induce apoptosis but sensitized ovarian cancer cells to TX. We then demonstrated that this sensitization mechanism was cell cycle independent and relied on i-CLU/Ku70 binding probably due to controlling the free amount of Ku70 available for DNA repair in the nucleus. Results from CLU immunehistochemistry in ovarian tumor tissues verified the retardation of nuclear CLU staining in the recurrent tumor even though their primary counterparts showed nuclear CLU staining. Thus, the controversial data on CLU function in chemo-response/resistance may be explained by a shift in the pattern of CLU expression and intracellular localization as well when tumor acquires chemoresistance.


PLOS ONE | 2014

Histone deacetylase inhibitors sensitize lung cancer cells to hyperthermia: involvement of Ku70/SirT-1 in thermo-protection.

Mohamed Kamel Hassan; Hidemichi Watari; Alaa-Eldin Salah-Eldin; Ahmed S. Sultan; Zainab Mohamed; Yoichiro Fujioka; Yusuke Ohba; Noriaki Sakuragi

This study describes the sensitization mechanism to thermal stress by histone deacetylase inhibitors (HDACIs) in lung cancer cells and shows that Ku70, based on its acetylation status, mediates the protection of lung cancer from hyperthermia (42.5°C, 1-6 hrs). Ku70 regulates apoptosis by sequestering pro-apoptotic Bax. However, its role in thermal stress is not fully understood. The findings showed that, pre-treating lung cancer cells with HDACIs, nicotinamide (NM) or Trichostatin A (TsA) or both significantly enhanced hyperthermia-induced Bax-dependent apoptosis in PC-10 cells. We found that hyperthermia induces SirT-1, Sirtuin, upregulation but not HDAC6 or SirT-3, therefore transfection with dominant negative SirT-1 (Y/H) also eliminated the protection and resulted in more cell death by hyperthermia, in H1299 cells through Bax activation. Hyperthermia alone primed lung cancer cells to apoptosis without prominent death. After hyperthermia Bax was upregulated, Bcl-2 was downregulated, the Bax/Bcl-2 ratio was inversed and Bax/Bcl-2 heterodimer was dissociated. Although hyperthermia did not affect total Ku70 expression level, it stimulated Ku70 deacetylation, which in turn could bind more Bax in the PC-10 cells. These findings suggest an escape mechanism from hyperthermia-induced Bax activation. To verify the role of Ku70 in this protection mechanism, Ku70 was silenced by siRNA. Ku70 silencing significantly sensitized the lung cancer cells to hyperthermia. The Ku70 KD cells underwent cytotoxic G1 arrest and caspase-dependant apoptosis when compared to scrambled transfectants which showed only G2/M cytostatic arrest in the cell lines investigated, suggesting an additional cell cycle-dependent, novel, role of Ku70 in protection from hyperthermia. Taken together, our data show a Ku70-dependent protection mechanism from hyperthermia. Targeting Ku70 and/or its acetylation during hyperthermia may represent a promising therapeutic approach for lung cancer.

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