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4. Polo-like Kinase 1 Predicts Lymph Node Metastasis in Middle Eastern Colorectal Cancer Patients; Its Inhibition Reverses 5-Fu Resistance in Colorectal Cancer Cells.

Author

Poyil, Pratheesh Kumar, Siraj, Abdul K., Padmaja, Divya, Parvathareddy, Sandeep Kumar, Alobaisi, Khadija, Thangavel, Saravanan, Begum, Rafia, Diaz, Roxanne, Al-Dayel, Fouad, and Al-Kuraya, Khawla S.

Subjects
*LYMPHATIC metastasis, *CARCINOGENESIS, *COLORECTAL cancer, *LOGISTIC regression analysis, *EPITHELIAL-mesenchymal transition
Abstract

Polo-like kinase 1 (PLK1) is a serine/threonine–protein kinase essential for regulating multiple stages of cell cycle progression in mammals. Aberrant regulation of PLK1 has been observed in numerous human cancers and is linked to poor prognoses. However, its role in the pathogenesis of colorectal cancer (CRC) in the Middle East remains unexplored. PLK1 overexpression was noted in 60.3% (693/1149) of CRC cases and was significantly associated with aggressive clinico-pathological parameters and p-ERK1/2 overexpression. Intriguingly, multivariate logistic regression analysis identified PLK1 as an independent predictor of lymph node metastasis. Our in vitro experiments demonstrated that CRC cells with high PLK1 levels were resistant to 5-Fu treatment, while those with low PLK1 expression were sensitive. To investigate PLK1′s role in chemoresistance, we used the specific inhibitor volasertib, which effectively reversed 5-Fu resistance. Interestingly, forced PLK1 expression activated the CRAF-MEK-ERK signaling cascade, while its inhibition suppressed this cascade. PLK1 knockdown reduced epithelial-to-mesenchymal transition (EMT) progression and stem cell-like traits in 5-Fu-resistant cells, implicating PLK1 in EMT induction and stemness in CRC. Moreover, silencing ERK1/2 significantly mitigated chemoresistance, EMT, and stemness properties in CRC cell lines that express PLK1. Furthermore, the knockdown of Zeb1 attenuated EMT and stemness, suggesting a possible link between EMT activation and the maintenance of stemness in CRC. Our findings underscore the pivotal role of PLK1 in mediating chemoresistance and suggest that PLK1 inhibition may represent a potential therapeutic strategy for the management of aggressive colorectal cancer subtypes. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Evaluating the Influence of Hashimoto's Thyroiditis on Clinico‐Pathological Characteristics and Prognostic Outcomes of Middle Eastern Differentiated Thyroid Carcinoma.

Author

Parvathareddy, Sandeep Kumar, Siraj, Abdul K., Siraj, Nabil, Ahmed, Saeeda O., Al-Sobhi, Saif S., Al-Dayel, Fouad, Al-Kuraya, Khawla S., and Falhammar, Henrik

Subjects
*AUTOIMMUNE thyroiditis, *THYROID gland tumors, *SYMPTOMS, *CHI-squared test, *DESCRIPTIVE statistics, *LONGITUDINAL method, *KAPLAN-Meier estimator, *STATISTICS, *DISEASE complications
Abstract

Objective. Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, represents the most prevalent autoimmune thyroid disorder globally. The potential influence of HT on the clinical and pathological attributes, as well as the clinical outcomes of differentiated thyroid carcinoma (DTC), remains a point of ongoing debate within the medical community. The central focus of this study was to analyze the influence of HT on clinico‐pathological characteristics and its prognostic impact in a large cohort of DTC from Middle Eastern ethnicity. Design, Patients, Measurements. An extensive analysis involving 1822 DTC patients was conducted to determine the association with clinico‐pathological characteristics as well as prognosis, using Chi‐square tests and Kaplan‐Meier curves. Results. 23.9% (435/1822) of DTC patients were diagnosed with HT. Univariate analysis revealed a positive correlation between presence of HT and clinico‐pathological factors such as female gender, younger age, and early stage tumor. In contrast, HT demonstrated a negative association with several aggressive clinical features, including extrathyroidal extension, distant metastasis, recurrent/persistent disease and high‐risk categorization by the American Thyroid Association (ATA) guidelines. Despite HT being associated with favorable clinico‐pathological features in Middle Eastern DTC patient, our study found no significant influence on overall survival or recurrence‐free survival. Conclusion. The finding of an association between HT and favorable clinico‐pathological characteristics, but lack of impact on prognosis, underscores the complexity of HT‐DTC relationship, necessitating further comprehensive research to fully understand these interactions. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population

Author

Siraj, Abdul K., Bu, Rong, Iqbal, Kaleem, Parvathareddy, Sandeep Kumar, Siraj, Nabil, Siraj, Sarah, Diaz, Mark Ranier F., Rala, Dionne Rae, Benito, Allianah D., Sabido, Maria Angelita, Al-Rasheed, Maha, Al-Obaisi, Khadija A.S., Al-Haqawi, Wael, Victoria, Ingrid G., Al Balawy, Wafaa, Abedalthagafi, Malak, Wakil, Salma Majid, Ajarim, Dahish, Mohammed, Shamayel, Alhussain, Turki, Tulbah, Asma, Al-Badawi, Ismail A., Al-Dayel, Fouad, and Al-Kuraya, Khawla S.

Published
2020
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15. PLK1 and FoxM1 expressions positively correlate in papillary thyroid carcinoma and their combined inhibition results in synergistic anti‐tumor effects

Author

Poyil, Pratheesh Kumar, primary, Siraj, Abdul K., additional, Padmaja, Divya, additional, Parvathareddy, Sandeep Kumar, additional, Thangavel, Saravanan, additional, Alobaisi, Khadija, additional, Diaz, Roxanne, additional, Begum, Rafia, additional, Haqawi, Wael, additional, Al‐Sobhi, Saif S., additional, Al‐Dayel, Fouad, additional, and Al‐Kuraya, Khawla S., additional

Published
2024
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16. PLK1 and PARP positively correlate in Middle Eastern breast cancer and their combined inhibition overcomes PARP inhibitor resistance in triple negative breast cancer

Author

Siraj, Abdul K., primary, Poyil, Pratheesh Kumar, additional, Padmaja, Divya, additional, Parvathareddy, Sandeep Kumar, additional, Alobaisi, Khadija, additional, Thangavel, Saravanan, additional, Diaz, Roxanne, additional, Begum, Rafia, additional, Almalik, Osama, additional, Al-Dayel, Fouad, additional, and Al-Kuraya, Khawla S., additional

Published
2024
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17. Predictive risk factors for distant metastasis in pediatric differentiated thyroid cancer from Saudi Arabia

Author

Parvathareddy, Sandeep Kumar, primary, Siraj, Abdul K., additional, Annaiyappanaidu, Padmanaban, additional, Siraj, Nabil, additional, Al-Rasheed, Maha, additional, Al-Haqawi, Wael, additional, Qadri, Zeeshan, additional, Siddiqui, Khawar, additional, Al-Sobhi, Saif S., additional, Al-Dayel, Fouad, additional, and Al-Kuraya, Khawla S., additional

Published
2023
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21. Expanding the spectrum of germline variants in cancer

Author

Siraj, Abdul K., Masoodi, Tariq, Bu, Rong, Parvathareddy, Sandeep Kumar, Al-Badawi, Ismail A., Al-Sanea, Nasser, Ashari, Luai H., Abduljabbar, Alaa, Alhomoud, Samar, Al-Sobhi, Saif S., Tulbah, Asma, Ajarim, Dahish, Alzoman, Khalid, Aljuboury, Muna, Yousef, Hussam Bin, Al-Dawish, Mohammed, Al-Dayel, Fouad, Alkuraya, Fowzan S., and Al-Kuraya, Khawla S.

Published
2017
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22. Overexpression of the pro‐protein convertase furin predicts prognosis and promotes papillary thyroid carcinoma progression and metastasis through RAF / MEK signaling

Author

Poyil, Pratheesh Kumar, primary, Siraj, Abdul K., additional, Padmaja, Divya, additional, Parvathareddy, Sandeep Kumar, additional, Diaz, Roxanne, additional, Thangavel, Saravanan, additional, Begum, Rafia, additional, Haqawi, Wael, additional, Al‐Mohanna, Falah Hassan, additional, Al‐Sobhi, Saif S., additional, Al‐Dayel, Fouad, additional, and Al‐Kuraya, Khawla S., additional

Published
2023
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24. X-linked inhibitor of apoptosis protein (XIAP) predicts disease-free survival in BRAFV600E mutant papillary thyroid carcinoma in middle eastern patients

Author

Parvathareddy, Sandeep Kumar, primary, Siraj, Abdul K., additional, Bu, Rong, additional, Iqbal, Kaleem, additional, Al-Rasheed, Maha, additional, Al-Haqawi, Wael, additional, Annaiyappanaidu, Padmanaban, additional, Siraj, Nabil, additional, Ahmed, Saeeda O., additional, Al-Sobhi, Saif S., additional, Al-Dayel, Fouad, additional, and Al-Kuraya, Khawla S., additional

Published
2022
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25. Lynch Syndrome Identification in Saudi Cohort of Endometrial Cancer Patients Screened by Universal Approach

Author

Bu, Rong, primary, Siraj, Abdul K., additional, Parvathareddy, Sandeep Kumar, additional, Iqbal, Kaleem, additional, Azam, Saud, additional, Qadri, Zeeshan, additional, Al-Rasheed, Maha, additional, Haqawi, Wael, additional, Diaz, Mark, additional, Alobaisi, Khadija, additional, Annaiyappanaidu, Padmanaban, additional, Siraj, Nabil, additional, AlHusaini, Hamed, additional, Alomar, Osama, additional, Al-Badawi, Ismail A., additional, Al-Dayel, Fouad, additional, and Al-Kuraya, Khawla S., additional

Published
2022
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26. Overexpression of the pro‐protein convertase furin predicts prognosis and promotes papillary thyroid carcinoma progression and metastasis through RAF/MEK signaling.

Author

Poyil, Pratheesh Kumar, Siraj, Abdul K., Padmaja, Divya, Parvathareddy, Sandeep Kumar, Diaz, Roxanne, Thangavel, Saravanan, Begum, Rafia, Haqawi, Wael, Al‐Mohanna, Falah Hassan, Al‐Sobhi, Saif S., Al‐Dayel, Fouad, and Al‐Kuraya, Khawla S.

Abstract

Furin belongs to the pro‐protein convertases (PCs) family and its aberrant expression has been documented in various types of cancers; however, its role in thyroid cancer remains unclear. We investigated the expression of furin in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC) patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. Furin overexpression was observed in 44.6% of all PTC cases and was significantly associated with aggressive clinicopathological parameters and poor outcomes. We show that the knockdown of FURIN suppresses tumor growth, proliferation, migration, invasion, spheroid growth, and progression of epithelial‐to‐mesenchymal transition (EMT) in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) mutant cells, whereas its overexpression in BRAF wild‐type PTC cell lines reversed the effect. FURIN knockdown in the BRAF mutant cell line led to reduced tumor growth and increased apoptosis. Mechanistically, FURIN knockdown led to MEK/ERK pathway suppression in BRAF mutant cells, although inhibition of MEK did not affect furin expression, which suggests that furin acts through the MEK/ERK pathway. Furthermore, our study revealed the synergistic antitumor effect of furin depletion and anti‐MEK inhibitor treatment. Overall, these results indicate that furin is an important prognostic marker in Middle Eastern PTC and that it plays a crucial role in BRAF‐associated MAP/ERK pathway activation and tumorigenesis. Furin inhibition could be a potential therapeutic target for aggressive PTC. [ABSTRACT FROM AUTHOR]

Published
2023
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30. Abstract 5280: TERT promoter mutations are an independent predictor of distant metastasis in Middle Eastern papillary thyroid microcarcinoma

Author

Ahmed, Saeeda Omer, primary, Siraj, Abdul K., additional, Parvathareddy, Sandeep K., additional, Iqbal, Kaleem, additional, Qadri, Zeeshan, additional, Al-Rasheed, Maha, additional, Siraj, Sarah, additional, Thangavel, Saravanan, additional, Diaz, Roxanne, additional, Benito, Allianah, additional, Victoria, Ingrid F., additional, and AlKuraya, Khawla S., additional

Published
2022
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32. Abstract 5177: Lymph node ratio is superior to AJCC N stage for predicting recurrence in papillary thyroid carcinoma

Author

Parvathareddy, Sandeep K., primary, Siraj, Abdul K., additional, Qadri, Zeeshan, additional, Ahmed, Saeeda O., additional, Siraj, Nabil, additional, DeVera, Felisa, additional, Annaiyappanaidu, Padmanaban, additional, Sabido, Maria A., additional, Haqawi, Wael, additional, Aldossari, Hassan, additional, and Al-Kuraya, Khawla S., additional

Published
2022
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34. Abstract 5839: Exome sequencing revealed comparable frequencies of RNF43 mutations and BRAF mutations in Middle Eastern colorectal cancer

Author

Bu, Rong, primary, Siraj, Abdul K., additional, Masoodi, Tariq, additional, Parvathareddy, Sandeep Kumar, additional, Iqbal, Kaleem, additional, Benito, Allianah D., additional, Siraj, Sarah, additional, Siraj, Nabil, additional, Rasheed, Maha Al, additional, Ahmed, Saeeda O., additional, AL-Haqaw, Wael, additional, Sabido, Maria Angelita, additional, Diaz, Mark Ranier, additional, Annaiyappanaidu, Padmanaban, additional, and Al-Kuraya, Khawla S., additional

Published
2022
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46. High Expression of Cyclin D1 is an Independent Marker for Favorable Prognosis in Middle Eastern Breast Cancer

Author

Siraj,Abdul K, Parvathareddy,Sandeep Kumar, Annaiyappanaidu,Padmanaban, Ahmed,Saeeda O, Siraj,Nabil, Tulbah,Asma, Al-Dayel,Fouad, Ajarim,Dahish, Al-Kuraya,Khawla S, Siraj,Abdul K, Parvathareddy,Sandeep Kumar, Annaiyappanaidu,Padmanaban, Ahmed,Saeeda O, Siraj,Nabil, Tulbah,Asma, Al-Dayel,Fouad, Ajarim,Dahish, and Al-Kuraya,Khawla S

Abstract

Abdul K Siraj,1,* Sandeep Kumar Parvathareddy,1,* Padmanaban Annaiyappanaidu,1 Saeeda O Ahmed,1 Nabil Siraj,1 Asma Tulbah,2 Fouad Al-Dayel,2 Dahish Ajarim,3 Khawla S Al-Kuraya1 1Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 2Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 3Department of Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia*These authors contributed equally to this workCorrespondence: Khawla S Al-KurayaHuman Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211, Saudi ArabiaTel +966 1-205-5167Fax +966 1-205-5170Email kkuraya@kfshrc.edu.saPurpose: The cyclin D1 protein regulates cell cycle progression which is mediated by its interactions with cyclin-dependent kinases. Over-expression of cyclin D1 has been observed in several human cancers. This study was conducted to evaluate cyclin D1 expression in a large cohort of Middle Eastern breast cancers and determine its prognostic significance.Patients and Methods: Cyclin D1 expression was assessed immunohistochemically and its association with clinico-pathological parameters was analyzed in 1003 breast cancer patients.Results: Cyclin D1 was over-expressed in 59.4% (596/1003) of cases and significantly associated with a subset of breast cancers having favorable prognostic features, such as low grade (p < 0.0001), low stage (p = 0.0276), estrogen receptor (p < 0.0001) and progesterone receptor positive (p < 0.0001) tumors. An inverse association was found with triple negative breast cancers (p < 0.0001). More importantly, cyclin D1 expression was an independent predictor of favorable overall survival in our cohort (hazard ratio = 0.70; 95% confidence interval = 0.50– 0.98; p = 0.0395). Also, tumors that highly expressed cyclin D1 had a longer recurrence-free su

Published
2021

47. HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer

Author

Al-Kuraya, Khawla, Novotny, Hedvika, Bavi, Prashant, Siraj, Abdul K., Uddin, Shahab, Ezzat, Adnan, Sanea, Nasser Al, Al-Dayel, Fouad, Al-Mana, Hadeel, Sheikh, Salwa S., Mirlacher, Martina, Tapia, Coya, Simon, Ronald, Sauter, Guido, Terracciano, Luigi, and Tornillo, Luigi

Subjects
Colorectal cancer -- Research, Colorectal cancer -- Genetic aspects, Gene amplification -- Research, Cancer -- Genetic aspects, Cancer -- Research, Health
Published
2007

48. Recurrent Somatic MAP2K1 Mutations in Papillary Thyroid Cancer and Colorectal Cancer

Author

Bu, Rong, primary, Siraj, Abdul K., additional, Masoodi, Tariq, additional, Parvathareddy, Sandeep Kumar, additional, Iqbal, Kaleem, additional, Al-Rasheed, Maha, additional, Haqawi, Wael, additional, Diaz, Mark, additional, Victoria, Ingrid G., additional, Aldughaither, Saud M., additional, Al-Sobhi, Saif S., additional, Al-Dayel, Fouad, additional, and Al-Kuraya, Khawla S., additional

Published
2021
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