研究miR-524-5p和miR-567治療在黑色素瘤與BRAF抑製劑的抗藥性黑色素瘤;Study of miR-524-5p and miR-567 in the progression of melanoma and BRAF inhibitor-resistant melanoma

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Title:	研究miR-524-5p和miR-567治療在黑色素瘤與BRAF抑製劑的抗藥性黑色素瘤;Study of miR-524-5p and miR-567 in the progression of melanoma and BRAF inhibitor-resistant melanoma
Authors:	阮氏梅香;Huong, Nguyen Thi Mai
Contributors:	系統生物與生物資訊研究所
Keywords:	黑色素瘤;BRAF抑製劑;抗藥性;微型ＲＮＡ;Melanoma;BRAF inhibitor;Resistant;microRNA
Date:	2022-07-25
Issue Date:	2022-10-04 11:15:44 (UTC+8)
Publisher:	國立中央大學
Abstract:	現在有許多在黑色素瘤治療的發展，例如靶向治療和免疫治療；但部分患者對於治療沒有效或對這些治療產生抗藥性。因此，需要開發一種替代策略，可進一步提高臨床效益。目前已知MAPK/ERK 路徑在黑色素瘤的發展中為主要作用。我們先前微陣列晶片 (microarray) 實驗的結果觀察到有 22 種miRNAs與 MAPK/ERK 訊息路徑有關。在此論文研究兩個miRNAs為miR-524-5p 和 miR-567 ，並想了解在黑色素瘤以及 BRAF 抑製劑的抗藥性黑色素瘤中功能影響。我們之前的研究表明， miR-524-5p 的過度表現，可抑制黑色素瘤細胞增殖。然而，miR-524-5p在BRAF抑製劑的抗藥性黑色素瘤中功能及機制仍然未知。因此，在本研究中，首先我們專注於 miR-524-5p 在 BRAF 抑製劑的抗藥性黑色素瘤細胞中的功能。我們的數據顯示，接受 BRAF 抑製劑治療為完全治癒 (complete response) 和長期治療後復發 (long-term partial response) 的患者中 miR-524-5p 的表現量與短期治療後復發 (short-term partial response) 患者相比更高。此發現證明 miR-524-5p 參與黑色素瘤患者對 BRAF 抑製劑的反應。值得注意的是，miR-524-5p 的過度表現抑制黑色素瘤細胞和動物實驗的發展。在抗藥性細胞中觀察到 MAPK/ERK 訊息路徑的重新激活，並且 miR-524-5p 的過度表現抑制抗藥性細胞中磷酸化的MEK1/2 和 ERK1/2訊息路徑的活性。 miR-567為另一個有潛力的 miRNA ，表現量在黑色素瘤細胞和組織中與黑色素細胞和痣相比較低。值得注意的是，與 miR-524-5p 的染色結果相比，miR-567 的染色表現更準確地區分黑色素瘤和痣組織。 miR-567的過度表現顯著抑制黑色素瘤細胞增殖、存活、非貼附性的生長、遷移和侵襲能力。此外，將黑色素瘤細胞中miR-567 直接調控 IGF1R、E2F1 和 Cyclin基因減弱 (knockdown)，可抑制細胞的增殖和存活。有趣的是，可藉由miR-567 的過度表現下調黑色素瘤細胞中的 MAPK/ERK 和 PI3K/AKT訊息路徑。此外，miR-567的過度表現抑制巨噬細胞誘導黑色素瘤細胞所促使腫瘤生長。以上所述為此研究對 miR-524-5p 和 miR-567 調控黑色素瘤發生和 BRAF 抑製劑的抗藥性在生物上作用和機制更加暸解。研究結果顯示，miR-524-5p 和 miR-567 不僅可以作為生物標誌物，也可作為預防黑色素瘤進展的潛在分子靶點。 ;Even more advancements in the treatment of melanoma such as target therapy and immunotherapy are now available; unfortunately, a subset of patients do not benefit or produced resistance to these approaches. Therefore, an urgent need to develop an alternative strategy should be investigated to further improve clinical benefits. It is well established that MAPK/ERK pathway plays a major role in the progression of melanoma. Interestingly, our previous microarray result observed that there are 22 miRNAs related to the status of MAPK/ERK pathway. In this context, we were interested in the functions of two candidate miRNAs, miR-524-5p and miR-567, in the development of melanoma and BRAF inhibitor-resistant melanoma. Our previous study showed that overexpression of miR-524-5p reduced the development of melanoma cells. However, the biological functions of miR-524-5p and its mechanism underlying BRAF inhibitor resistance are still unknown. Therefore, in this study, we focused on the functions of miR-524-5p in BRAF inhibitor-resistant melanoma cells. The results showed that expression of miR-524-5p was higher in complete response and long-term partial response as compared to short-term partial response and progressive disease in patients treated with BRAF inhibitors. This finding suggested that miR-524-5p was involved in the response of melanoma patients to BRAF inhibitors. Of note, overexpression of miR-524-5p reduced the development of melanoma in vivo and in vitro. Reactivation of MAPK/ERK pathway was observed in resistant cells and overexpression of miR-524-5p downregulated the activity of this pathway by decreasing the phosphorylation of MEK1/2 and ERK1/2. Expression of miR-567, another potential miRNA candidate, was decreased in melanoma cells and melanoma tissues as compared to melanocyte cells and nevus tissues. Of note, staining expression of miR-567 was more accurately differentiate between melanoma and nevus tissues as compared to staining of miR-524-5p. Overexpression of miR-567 in melanoma cells significantly reduced proliferation, survival, anchorage-independent growth, migratory, and invasive abilities. In addition, knockdown of miR-567 direct targets, IGF1R, E2F1, and Cyclin B2, attenuated proliferation and survival of melanoma cells. Interestingly, introduction of miR-567 downregulated MAPK/ERK and PI3K/AKT pathways in melanoma cells. Moreover, overexpression of miR-567 reduced the promoting tumor growth of melanoma cells induced by macrophages, indicating the involvement of miR-567 in tumor microenvironment. In conclusion, these results increased the knowledge about the biological roles and mechanisms underlying miR-524-5p and miR-567 mediated tumorigenesis and BRAF inhibitor resistance. The findings suggested that miR-524-5p and miR-567 could be served not only as biomarkers but also as potential molecular targets for prevention of melanoma progression.
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