Expression of p63 Cytoplasmic Aberrance, Notch1, and ALDH1A1 in Prostate Lesions; Their Association with Pathological Diagnosis, Cancer Cells Proliferation, and Apoptosis.

Paranita Ferronika, dr. Harijadi, Sp.PA(K)

2012 | Tesis | S2 Ilmu Patologi Anatomi

Latar Belakang: Kanker prostat di Indonesia menduduki peringkat ketiga di antara penyakit kanker pada laki-laki dan peringkat kelima di antara kematian akibat kanker pada laki-laki. Sangat diperlukan petanda biologis yang dapat mengidentifikasi agresifitas kanker pada lesi awal yang kemudian dapat membantu pemilihan terapi yang tepat, guna mengurangi kematian. Sel punca pada kelenjar prostat telah terbukti memiliki peran dalam inisiasi, progresivitas, dan metastasis sel kanker, meskipun masih dalam kontroversi. Pemeliharaan populasi sel punca normal atau sel reserve di beberapa epitel termasuk prostat diketahui diregulasi oleh p63 dan Notch1. Sinyal Notch mempunyai peran penting dalam mempertahankan fenotip sel punca. Perubahan expresi p63 dianggap mempunyai peran onkogenik pada kanker prostat. Peran onkogenik ini juga diusulkan berhubungan dengan ekspresi Notch1 yang tinggi. Tujuan: Untuk mempelajari peran sel punca kanker dan regulasinya dalam inisiasi dan perkembangan kanker prostat dengan meneliti hubungan petanda tersebut dengan diagnosis patologi termasuk skor Gleason, tingkat proliferasi sel, dan apoptosis. Metode: Studi ini dilakukan secara cross-sectional dalam periode tahun 2009- 2010, dengan pengecatan IHC pada 79 jaringan blok parafin dengan diagnosis benign prostatic hyperplasia, prostatic intraepithelial neoplasia derajat tinggi, dan kanker prostat dengan skor Gleason rendah dan tinggi. Ekspresi ALDH1A1, p63 sitoplasma, dan Notch1 diteliti di tiap grup lesi prostat berbeda. Hubungan antara tiga petanda tersebut dianalisa dengan Chi-square. Hubungan petanda tersebut dengan diagnosis patologi dianalisa dengan Chi-square. Hubungan ekspresi Notch1 dan ALDH1A1 dengan tingkat proliferasi sel (Ki-67) dianalisa dengan Mann-Whitney. Sedangkan hubungan p63 sitoplasma dengan Ki-67 dan cleaved caspase 3 dianalisa dengan Kruskal-Wallis. Statistik dianggap signifikan jika nilai p<0,05. Hasil: Usia rata-rata pasien saat terdiagnosis adalah 69,89 tahun. Didapatkan hubungan antara ekspresi ektopik p63 sitoplasma, Notch1, dan ALDH1A1(Chisquare, semua petanda p<0.001). Ekspresi ALDH1A1, ektopik p63 sitoplasma, dan Notch1 didapati berhubungan signifikan dengan diagnosis patologi (Chisquare, semua petanda p<0.001). Terlebih lagi, pada penelitian ini juga didapatkan ekspresi p63 sitoplasma dan Notch1 mempunyai hubungan signifikan dengan tingkat proliferasi sel pada sel kanker (Kruskall-Wallis, p=0.001 dan Mann- Whitney, p=0.009). Hanya p63 sitoplasma yang mempunyai hubungan dengan tingkat apoptosis (Kruskall-Wallis, p=0.015). Kesimpulan: Ekspresi ALDH1A1, ektopik p63 sitoplasma, and Notch1 diusulkan mempunyai peranan penting dalam progresi kanker prostat dan kemungkinan dapat digunakan sebagai petanda molekular. Interaksi antara komponenkomponen tersebut, walaupun masih dalam kontroversi, penting untuk digarisbawahi dan diteliti lebih lanjut.

Background: Prostate cancer in Indonesia is the third rank cancer among male and the fifth rank cancer mortality among male. Prognostic markers that can identify aggressive prostate cancer in early lesion which can help select appropriate therapy to finally reduce the mortality are therefore urgently needed. It has been proven that stem cell in prostate gland have a role in initiation, progression, and metastasis of cancer cells, although still in controversy. Maintenance of normal stem cell or reserve cell populations in several epithelia including prostate gland were shown to be regulated by p63 and Notch1. The alteration of p63 expression is considered to have an oncogenic role in prostate cancer. This oncogenic role was also proposed associated with Notch1 expression. Objective: To investigate the role of cancer stem cell and its regulation in initiation and progression of prostate cancer by investigating its association with pathological diagnosis including Gleason score, cell proliferation, and apoptosis. Methods: Cross-sectional study in period of 2009-2010 was performed, in which totally 79 paraffin embedded tissues consisting of Benign Prostatic Hyperplasia, High Grade Prostatic Intraepithelial Neoplasia, and prostate cancer were investigated using IHC staining. The expressions of ALDH1A1, cytoplasmic p63, and Notch1 in different group of prostate lesion were investigated. The association among those three markers was analyzed by Chi-square test. The association of those markers with pathological diagnosis was analyzed by Chisquare test. The association of ALDH1A1 and Notch1 expression with cell proliferation rate (Ki-67) and apoptotic marker (cleaved caspase 3) was analyzed by Mann-Whitney test. Meanwhile, the association of cytoplasmic p63 with Ki67 and cleaved caspase 3 was analyzed by Kruskal-Wallis test. A p-value of <0.05 was considered statistically significant. Results: Patients had mean age at the diagnosis of 69.89 years. Association were found between cytoplasmic p63, Notch1 and ALDH1A1 expression (Chi-square, both p<0.001). ALDH1A1, ectopic cytoplasmic p63, and Notch1 were found to be significantly associated with pathological diagnosis, including Gleason score (Chi-square, p<0.001, p=0.006, and p<0.001 respectively). Moreover, it is also found in this study that cytoplasmic p63 and Notch1 were significantly associated with frequency of proliferating cells in prostate cancers (Kruskall-Wallis, p=0.001 and Mann-Whitney, p=0.009 respectively). Only cytoplasmic p63 that was significantly associated with apoptotic rate (Kruskall-Wallis, p=0.015). Conclusion: The expression of ALDH1A1, p63 cytoplasmic aberrance, and Notch1 is suggested to be important in prostate cancer progression and may be used as molecular markers. The interaction among those components, although still clouded by controversy, needed to be outlined and further investigated.

Kata Kunci : p63, Notch1, ALDH1A1, sel punca kanker, kanker prostat