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  1. Dysregulation of non-histone molecule miR205 and LRG1 post-transcriptional de-regulation by SETD1A in triple negative breast cancer
    Mohamad Hanif EA
    Mol Biol Rep, 2019 Dec;46(6):6617-6624.
    PMID: 31552595 DOI: 10.1007/s11033-019-05079-w
    FEC chemo-resistance in triple negative breast cancer (TNBC) remains a challenge. Therefore it is crucial to determine the right treatment regime by understanding molecular mechanisms of driver regulators involved in the progression of TNBCs. This study aims to understand SETD1A mechanisms in TNBC development in two TNBC cell lines. SETD1A was transiently transfected in MDA-MB-468 (FEC good prognosis) and Hs578T (FEC poor prognosis). Regulation of potential targets miR205, EMT marker ZEB1 and LRG1 and proliferative marker Ki-67 were tested by RqPCR to elucidate SETD1A interactions. This study displayed significant recovery of miR205 with SETD1A depletion and reduction of ZEB1 in MDA-MB-468. However, ZEB1 remained unchanged in Hs578T indicating ZEB1 regulation may be outcompeted by other mechanisms associated with aggressive cell line characteristics and the expression of endogenous ZEB1 was relatively high in Hs578T. Elevation of LRG1 and declined Ki-67 were observed by SETD1A knocked down. Enhanced expression was observed by LRG1 in Hs578T and not in MDA-MB-468 suggesting LRG1 contributed to distinct poor FEC outcome in TNBCs. The underlying mechanism of SETD1A in miR205/ZEB1/Ki-67/LRG1 axis needs further evaluation. Whether abrogation of the pathway is indeed associated with transcriptional or post-transcriptional activation in TNBC cell lines models, clearly validation in clinical samples is warranted to achieve its prognostic and therapeutic values in TNBCs.
  2. Overview on Epigenetic Re-programming: A Potential Therapeutic Intervention in Triple Negative Breast Cancers
    Mohamad Hanif EA, Shah SA
    Asian Pac J Cancer Prev, 2018 Dec 25;19(12):3341-3351.
    PMID: 30583339
    Breast cancer treatments leads to variable responses. Hormonal therapy is beneficial to receptor positive breast cancer
    subtypes and display better clinical outcome than triple negative breast cancers (TNBCs) with FEC (5-Fluorouracil,
    Epirubicin and Cyclophosphamide) the mainstay chemotherapy regiment. Owning to their negative expressions of
    estrogen (ER), progesterone (PR) and HER2 receptors, disease recurrence and metastasis befalls some patients indicating
    resistance to FEC. Involvement of epigenetic silencing through DNA methylation, histone methylation, acetylation and
    sumoylation may be the key player in FEC chemoresistance. Epigenetic and molecular profiling successfully classified
    breast cancer subtypes, indicating potential driver mechanisms to the progression of TNBCs but functional mechanisms
    behind chemoresistance of these molecular markers are not well defined. Several epigenetic inhibitors and drugs have
    been used in the management of cancers but these attempts are mainly beneficial in hematopoietic cancers and not
    specifically favourable in solid tumours. Hypothetically, upon administration of epigenetic drugs, recovery of tumour
    suppressor genes is expected. However, high tendency of switching on global metastatic genes is predicted. Polycomb
    repressive complex (PRC) such as EZH2, SETD1A, DNMT, is known to have repressive effects in gene regulation and
    shown to inhibit cell proliferation and invasion in breast cancers. Individual epigenetic regulators may be an option
    to improve chemo-drug delivery in cancers. This review discussed on molecular signatures of various breast cancer
    subtypes and on-going attempts in understanding underlying molecular mechanisms of epigenetic regulators as well
    as providing insights on possible ways to utilize epigenetic enzymes/inhibitors with responses to chemotherapeutic
    drugs to re-program cellular and biological outcome in TNBCs.
  3. Identifying miRNA as biomarker for breast cancer subtyping using association rule
    Md Zaki FA, Mohamad Hanif EA
    Comput Biol Med, 2024 Aug;178:108696.
    PMID: 38850957 DOI: 10.1016/j.compbiomed.2024.108696
    - This paper presents a comprehensive study focused on breast cancer subtyping, utilizing a multifaceted approach that integrates feature selection, machine learning classifiers, and miRNA regulatory networks. The feature selection process begins with the CFS algorithm, followed by the Apriori algorithm for association rule generation, resulting in the identification of significant features tailored to Luminal A, Luminal B, HER-2 enriched, and Basal-like subtypes. The subsequent application of Random Forest (RF) and Support Vector Machine (SVM) classifiers yielded promising results, with the SVM model achieving an overall accuracy of 76.60 % and the RF model demonstrating robust performance at 80.85 %. Detailed accuracy metrics revealed strengths and areas for refinement, emphasizing the potential for optimizing subtype-specific recall. To explore the regulatory landscape in depth, an analysis of selected miRNAs was conducted using MIENTURNET, a tool for visualizing miRNA-target interactions. While FDR analysis raised concerns for HER-2 and Basal-like subtypes, Luminal A and Luminal B subtypes showcased significant miRNA-gene interactions. Functional enrichment analysis for Luminal A highlighted the role of Ovarian steroidogenesis, implicating specific miRNAs such as hsa-let-7c-5p and hsa-miR-125b-5p as potential diagnostic biomarkers and regulators of Luminal A breast cancer. Luminal B analysis uncovered associations with the MAPK signaling pathway, with miRNAs like hsa-miR-203a-3p and hsa-miR-19a-3p exhibiting potential diagnostic and therapeutic significance. In conclusion, this integrative approach combines machine learning techniques with miRNA analysis to provide a holistic understanding of breast cancer subtypes. The identified miRNAs and associated pathways offer insights into potential diagnostic biomarkers and therapeutic targets, contributing to the ongoing efforts to improve breast cancer diagnostics and personalized treatment strategies.
  4. Fulltext Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect
    Lim SM, Mohamad Hanif EA, Chin SF
    Cell Biosci, 2021 Mar 20;11(1):56.
    PMID: 33743781 DOI: 10.1186/s13578-021-00570-z
    Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.
  5. Silencing of ZFP36L2 increases sensitivity to temozolomide through G2/M cell cycle arrest and BAX mediated apoptosis in GBM cells
    Che Mat MF, Mohamad Hanif EA, Abdul Murad NA, Ibrahim K, Harun R, Jamal R
    Mol Biol Rep, 2021 Feb;48(2):1493-1503.
    PMID: 33590411 DOI: 10.1007/s11033-021-06144-z
    Despite the advancements in primary brain tumour diagnoses and treatments, the mortality rate remains high, particularly in glioblastoma (GBM). Chemoresistance, predominantly in recurrent cases, results in decreased mean survival of patients with GBM. We aimed to determine the chemosensitisation and oncogenic characteristics of zinc finger protein 36-like 2 (ZFP36L2) in LN18 GBM cells via RNA interference (RNAi) delivery. We conducted a meta-analysis of microarray datasets and RNAi screening using pooled small interference RNA (siRNA) to identify the druggable genes responsive to GBM chemosensitivity. Temozolomide-resistant LN18 cells were used to evaluate the effects of gene silencing on chemosensitisation to the sub-lethal dose (1/10 of the median inhibitory concentration [IC50]) of temozolomide. ZFP36L2 protein expression was detected by western blotting. Cell viability, proliferation, cell cycle and apoptosis assays were carried out using commercial kits. A human apoptosis array kit was used to determine the apoptosis pathway underlying chemosensitisation by siRNA against ZFP36L2 (siZFP36L2). Statistical analyses were performed using one-way analysis of variance; p > 0.05 was considered significant. The meta-analysis and RNAi screening identified ZFP36L2 as a potential marker of GBM. ZFP36L2 knockdown significantly induced apoptosis (p 
  6. Prospective Advances in Circular RNA Investigation
    Sulaiman SA, Abdul Murad NA, Mohamad Hanif EA, Abu N, Jamal R
    Adv Exp Med Biol, 2018 9 28;1087:357-370.
    PMID: 30259380 DOI: 10.1007/978-981-13-1426-1_28
    circRNAs have emerged as one of the key regulators in many cellular mechanisms and pathogenesis of diseases. However, with the limited knowledge and current technologies for circRNA investigations, there are several challenges that need to be addressed for. These include challenges in understanding the regulation of circRNA biogenesis, experimental designs, and sample preparations to characterize the circRNAs in diseases as well as the bioinformatics pipelines and algorithms. In this chapter, we discussed the above challenges and possible strategies to overcome those limitations. We also addressed the differences between the existing applications and technologies to study the circRNAs in diseases. By addressing these challenges, further understanding of circRNAs roles and regulations as well as the discovery of novel circRNAs could be achieved.
  7. Fulltext The rs9340799 polymorphism of the estrogen receptor alpha (ESR1) gene and its association with breast cancer susceptibility
    Tan SC, Low TY, Mohamad Hanif EA, Sharzehan MAK, Kord-Varkaneh H, Islam MA
    Sci Rep, 2021 Sep 20;11(1):18619.
    PMID: 34545128 DOI: 10.1038/s41598-021-97935-8
    The ESR1 rs9340799 polymorphism has been frequently investigated with regard to its association with breast cancer (BC) susceptibility, but the findings have been inconclusive. In this work, we aimed to address the inconsistencies in study findings by performing a systematic review and meta-analysis. Eligible studies were identified from the Web of Science, PubMed, Scopus, China National Knowledge Infrastructure, VIP and Wanfang databases based on the predefined inclusion and exclusion criteria. The pooled odds ratio (OR) was then calculated under five genetic models: homozygous (GG vs. AA), heterozygous (AG vs. AA), dominant (AG + GG vs. AA), recessive (GG vs. AA + AG) and allele (G vs. A). Combined results from 23 studies involving 34,721 subjects indicated a lack of significant association between the polymorphism and BC susceptibility (homozygous model, OR = 1.045, 95% CI 0.887-1.231, P = 0.601; heterozygous model, OR = 0.941, 95% CI 0.861-1.030, P = 0.186; dominant model, OR = 0.957, 95% CI 0.875-1.045, P = 0.327; recessive model, OR = 1.053, 95% CI 0.908-1.222, P = 0.495; allele model, OR = 0.987, 95% CI 0.919-1.059, P = 0.709). Subgroup analyses by ethnicity, menopausal status and study quality also revealed no statistically significant association (P > 0.05). In conclusion, our results showed that the ESR1 rs9340799 polymorphism was not associated with BC susceptibility, suggesting its limited potential as a genetic marker for BC.
  8. Fulltext Parvimonas micra infection enhances proliferation, wound healing, and inflammation of a colorectal cancer cell line
    Hatta MNA, Mohamad Hanif EA, Chin SF, Low TY, Neoh HM
    Biosci Rep, 2023 Jun 28;43(6).
    PMID: 37218575 DOI: 10.1042/BSR20230609
    The gut microbiota Parvimonas micra has been found to be enriched in gut mucosal tissues and fecal samples of colorectal cancer (CRC) patients compared with non-CRC controls. In the present study, we investigated the tumorigenic potential of P. micra and its regulatory pathways in CRC using HT-29, a low-grade CRC intestinal epithelial cell. For every P. micra-HT-29 interaction assay, HT-29 was co-cultured anaerobically with P. micra at an MOI of 100:1 (bacteria: cells) for 2 h. We found that P. micra increased HT-29 cell proliferation by 38.45% (P=0.008), with the highest wound healing rate at 24 h post-infection (P=0.02). In addition, inflammatory marker expression (IL-5, IL-8, CCL20, and CSF2) was also significantly induced. Shotgun proteomics profiling analysis revealed that P. micra affects the protein expression of HT-29 (157 up-regulated and 214 down-regulated proteins). Up-regulation of PSMB4 protein and its neighbouring subunits revealed association of the ubiquitin-proteasome pathway (UPP) in CRC carcinogenesis; whereas down-regulation of CUL1, YWHAH, and MCM3 signified cell cycle dysregulation. Moreover, 22 clinically relevant epithelial-mesenchymal transition (EMT)-markers were expressed in HT-29 infected with P. micra. Overall, the present study elucidated exacerbated oncogenic properties of P. micra in HT-29 via aberrant cell proliferation, enhanced wound healing, inflammation, up-regulation of UPPs, and activation of EMT pathways.
  9. The potential roles of lncRNA TINCR in triple negative breast cancer
    Azman AA, Siok-Fong C, Rajab NF, Md Zin RR, Ahmad Daud NN, Mohamad Hanif EA
    Mol Biol Rep, 2023 Sep;50(9):7909-7917.
    PMID: 37442895 DOI: 10.1007/s11033-023-08661-5
    Triple negative breast cancer (TNBC) is the most aggressive intrinsic breast cancer subtype characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and low levels of human epidermal growth factor receptor 2 (HER2). The complex nature of TNBC has resulted in little therapeutic progress for the past several decades. The standard of care remains the FEC cocktail (5-fluorouracil (5-FU), epirubicin and cyclophosphamide). However, early relapse and metastasis in TNBC patients persists in causing dismal clinical outcomes. Due to complex heterogeneity features of TNBC, identifying the biomarker associated to the chemoresistance remains a challenge. The emergence of the long non-coding RNA (lncRNA) as a potential signature may have proven to be a new deterrent to diagnostic and treatment options. Previous studies unveiled the associations of lncRNA in the development of TNBCs whereby the aggressiveness and response to therapies may be associated by the abrogation of the molecular mechanism lncRNA. Terminal differentiation induced ncRNA (TINCR) is a lncRNA which have been linked with many cancers including TNBC. The expression and behavior of TINCR may exert unfavorable outcome in TNBCs. Nevertheless, the underlying molecular mechanism of TINCR in driving chemoresistance in TNBC is not well understood. This review will highlight the potential molecular mechanisms of TINCR in TNBC chemoresistance and how it can serve as a future potential prognostic and therapeutic target for a better treatment intervention.
  10. Fulltext Pathogens and Carcinogenesis: A Review
    Hatta MNA, Mohamad Hanif EA, Chin SF, Neoh HM
    Biology (Basel), 2021 Jun 15;10(6).
    PMID: 34203649 DOI: 10.3390/biology10060533
    Cancer is a global health problem associated with genetics and unhealthy lifestyles. Increasingly, pathogenic infections have also been identified as contributors to human cancer initiation and progression. Most pathogens (bacteria, viruses, fungi, and parasites) associated with human cancers are categorized as Group I human carcinogens by the International Agency for Research on Cancer, IARC. These pathogens cause carcinogenesis via three known mechanisms: persistent infection that cause inflammation and DNA damage, initiation of oncogene expression, and immunosuppression activity of the host. In this review, we discuss the carcinogenesis mechanism of ten pathogens, their implications, and some future considerations for better management of the disease. The pathogens and cancers described are Helicobacter pylori (gastric cancer), Epstein-Barr virus (gastric cancer and lymphoma), Hepatitis B and C viruses (liver cancer), Aspergillus spp. (liver cancer), Opisthorchis viverrine (bile duct cancer), Clonorchis sinensis (bile duct cancer), Fusobacterium nucleatum (colorectal cancer), Schistosoma haematobium (bladder cancer); Human Papillomavirus (cervical cancer), and Kaposi's Sarcoma Herpes Virus (Kaposi's sarcoma).
  11. Microsatellite Instability and Altered Expressions of MLH1 and MSH2 in Gastric Cancer
    Haron NH, Mohamad Hanif EA, Abdul Manaf MR, Yaakub JA, Harun R, Mohamed R, et al.
    Asian Pac J Cancer Prev, 2019 Feb 26;20(2):509-517.
    PMID: 30803214
    Introduction: Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) of genes especially MLH1 and MSH2. It is frequently involved in the carcinogenesis of various tumours including gastric cancer (GC). However, MSI in GCs have not been reported in Malaysia before. Objective: This study was conducted to determine the microsatellite instability (MSI) status in gastric cancer by microsatellite analysis, sequencing, its association with MLH1 and MSH2 protein expression and H.pylori infection by immunohistochemistry. Method: A total of 60 gastric cancer cases were retrieved. DNA was extracted from paired normal and tumour tissues while MLH1 and MSH2 protein expression as well as H. pylori status were determined by IHC staining. For microsatellite analysis, polymerase chain reaction (PCR) was performed for paired tissue samples using a panel of five microsatellite markers. MSI-positive results were subjected for DNA sequencing to assess mutations in the MLH1 and MSH2 genes. Results: Microsatellite analysis identified ten MSI positive cases (16.7%), out of which only six cases (10.3%) showed absence of MLH1 (n=3) or MSH2 (n=3) protein expression by IHC. The most frequent microsatellite marker in MSI positive cases was BAT26 (90%). Nine of ten MSI positive cases were intestinal type with one diffuse and all were located distally. H. pylori infection was detected in 13 of 60 cases (21.7%) including in three MSI positive cases. All these results however were not statistically significant. Our sequencing data displayed novel mutations. However these data were not statistically correlated with expression levels of MLH1 and MSH2 proteins by IHC. This may be due to small sample size to detect small or moderately sized effects. Conclusion: The frequency of MSI in this study was comparable with published results. Determination of affected MMR genes by more than two antibodies may increase the sensitivity of IHC to that of MSI analysis.
  12. Fulltext COVID-19 in Malaysia: exposure assessment and prevention practices among healthcare workers at a teaching hospital
    Muhammad Azami NA, Abdul Murad NA, Mohammed Nawi A, Salleh SA, Periyasamy P, Kori N, et al.
    J Infect Dev Ctries, 2021 12 31;15(12):1816-1824.
    PMID: 35044938 DOI: 10.3855/jidc.15277
    INTRODUCTION: During the second wave of the coronavirus disease 19 (COVID-19) pandemic, Malaysia reported several COVID-19 clusters related to healthcare workers. Thus, addressing and understanding the risk of exposure in healthcare workers is important to prevent future infection and reduce secondary COVID-19 transmission within the healthcare settings. In this study, we aim to assess exposure and prevention practices against COVID-19 among healthcare workers at the Hospital Canselor Tuanku Muhriz, a university teaching hospital based in Kuala Lumpur, Malaysia.

    METHODOLOGY: A total of 571 healthcare workers at COVID-19 and non-COVID-19 wards as well as the emergency department and laboratory staff at COVID-19 testing labs were recruited. The presence of novel human coronavirus (SARS-CoV-2) and IgM/IgG antibodies were confirmed in all healthcare workers. The healthcare workers responded to an online Google Forms questionnaire that evaluates demographic information and comorbidities, exposure and adherence to infection prevention and control measures against COVID-19. Descriptive analysis was performed using Statistical Package for the Social Sciences 24.0.

    RESULTS: Three healthcare workers (0.5%) tested positive for SARS-CoV-2, while the remaining 568 (99.5%) were negative. All were negative for IgM and IgG antibodies during recruitment (day 1) and follow-up (day 15). More than 90% of the healthcare workers followed infection prevention and control practices recommendations regardless of whether they have been exposed to occupational risk for COVID-19.

    CONCLUSIONS: The healthcare workers' high level of adherence to infection prevention practices at this hospital helped reduce and minimize their occupational exposure to COVID-19.

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