Correlation Between Endothelin-1/Endothelin A Receptor Axis And Heparanase Expression In Ovarian Carcinoma

NUNGKI ANGGOROWATI, dr. Prijono Tirtoprodjo, Sp.PA(K); dr. Ahmad Ghozali, Sp.PA(K); dr. FX. Ediati Triningsih, Sp.PA(K)

2015 | Tesis | SP ILMU PATOLOGI ANATOMI

Karsinoma ovarium merupakan keganasan ginekologis yang menyebabkan kematian tersering karena mempunyai sifat mudah bermetastasis. Berdasarkan histopatologi, karsinoma ovarium terdiri dari empat subtipe yaitu tipe serosa, musinosa, endometrioid, dan sel jernih. Subtipe ini mempunyai perbedaan patogenesis molekuler dan prognosis. Heparanase berkorelasi dengan ketahanan hidup pada karsinoma ovarium. Ekspresi heparanase dan aksis endothelin-1/reseptor endothelin A (ET-1/ETAR) meningkat pada keganasan dan berperan pada progresivitas, migrasi, invasi, metastasis, dan angiogenesis tumor. Penelitian ini menganalisis ekspresi dan korelasi antara heparanase dan aksis ET-1/ETAR pada neoplasma ovarium baik jinak maupun ganas. Umur pasien pada penelitian ini antara 15 to 71 tahun (median umur 49.5 tahun). Histoscore heparanase dan ETAR, ekspresi mRNA prepro endothelin-1 (ppET-1) and ETAR, dan persentase Ki-67 lebih tinggi secara bermakna pada karsinoma ovarium dibandingkan dengan kelompok jinak atau borderline, tanpa memperhatikan tipe histopatologi. Histoscore immunohistokimia heparanase berkorelasi dengan histoscore ETAR (r= 0.484, P=0.007) dan ekspresi mRNA ETAR (r=0.551, P=0.003). Ekspresi mRNA ppET-1 berkorelasi dengan ekspresi mRNA ETAR and histoscore ETAR (r=0.603, P=0.001 and r=0.455, P=028; respectively). Neoplasma ovarium dengan ekspresi mRNA ppET-1 yang tinggi cenderung mempunyai ekspresi mRNA heparanase yang tinggi, walaupun hanya berkorelasi lemah (r=0.354, P=0.07). Ki-67 berkorelasi dengan heparanase and histoscore ETAR (r=0.381, P=0.038; r=0.477, P=0.008, respectively). Korelasi antara heparanase, ppET-1, and ETAR pada studi ini menunjukkan kemungkinan adanya crosstalk antara aksis ET-1/ETAR and heparanase. Hal ini juga menunjukkan kemungkinan peningkatan aktivitas antitumor dan antimetastasis dari inhibitor ETAR dan heparanase.

Ovarian carcinoma is one of the leading causes of mortality from gynecologic malignancy as a result of prompt metastatic behavior. There are four major histopathological subtypes of ovarian carcinoma such as serous, mucinous, endometrioid, and clear cell types. These subtypes have distinctive molecular pathogenesis and prognosis. Heparanase correlates with poor survival in ovarian carcinoma. Heparanase and endothelin-1/endothelin A receptor (ET-1/ETAR) axis were upregulated in malignancy and have roles in tumor progression, migration, invasion, metastasis and angiogenesis. The present study analyzed the expression and correlation of heparanase and ET-1/ETAR axis in 30 patients with ovarian neoplasm both benign and malignant. The age ranged from 15 to 71 y (median age 49.5 y). The heparanase and ETAR histoscores, prepro endothelin-1 (ppET-1) and ETAR mRNA levels, as well as Ki- 67 were significantly higher in ovarian carcinoma compared to the benign or borderline group, regardless of the histopathological type. Heparanase immunohistochemical histoscore was correlated with ETAR histoscore (r= 0.484, P=0.007) and ETAR mRNA level (r=0.551, P=0.003). The level of ppET-1 mRNA was correlated with both ETAR mRNA level and ETAR histoscore (r=0.603, P=0.001 and r=0.455, P=028; respectively). The ovarian neoplasms with high ppET-1 mRNA levels also tended to have high heparanase mRNA levels, yet it only had a weak correlation (r=0.354, P=0.07). Ki-67 was correlated with heparanase and ETAR histoscores (r=0.381, P=0.038; r=0.477, P=0.008, respectively). The correlation between heparanase, ppET-1, and ETAR in the current study marked possible crosstalk between heparanase and the ET-1/ETAR axis. Furthermore it may enhance the antitumor and antimetastatic activities of ETAR and heparanase inhibitors.

Kata Kunci : karsinoma ovarium, subtipe histopatologi, aksis ET-1/ETAR, heparanase, Ki-67, ovarian carcinoma, histopathological subtype, ET-1/ETAR axis, heparanase, Ki- 67