Oncogene c-Myc-dependent pathways in cutaneous melanoma03

描述（由申请人提供）：恶性黑色素瘤是最具侵袭性的人类癌症之一。它的转移能力使得黑色素瘤极难治愈，因此，转移性黑色素瘤患者的中位生存期只有8.5个月。黑色素瘤发生的分子机制尚不清楚，与黑色素瘤进展的特定阶段相关的可靠标志物尚未确定。在大约60%和20%的黑色素瘤中分别发现了激活BRAF （V600E）和NRAS （Q61R）的癌蛋白氨基酸替换。有趣的是，同样的突变在人类良性痣（正常黑色素细胞聚集）的样本中发现的频率更高。在培养的正常人类黑素细胞中，BRAFV600E或NRASQ61R诱导的衰老表型与痣中观察到的衰老表型几乎相同。因此，起源于痣的黑素瘤一定具有克服癌基因诱导的衰老（OIS）的机制，但这种机制的性质在很大程度上是未知的。我们最近证明，与小鼠或人类成纤维细胞不同，p53或p16INK4A肿瘤抑制因子的消耗不足以克服人类黑素细胞中的OIS。相反，我们已经证明癌蛋白C-MYC的异位表达显著抑制BRAFV600E-和NRASQ61R-在这些细胞中诱导的衰老，但效率较低。此外，我们首次证明，在人类转移性黑色素瘤细胞中，C-MYC的缺失重新激活了休眠的BRAFV600E或nrasq61特异性衰老程序，从而表明C-MYC是黑色素瘤进展过程中持续抑制OIS所必需的。C-MYC是一种转录因子，调节参与许多细胞过程的多种基因的表达。它在绝大多数人类恶性肿瘤中过度表达，包括黑色素瘤。C-MYC抑制正常人类黑色素细胞中的OIS或RS，或使人类黑色素瘤细胞中的衰老程序处于休眠状态的机制尚不清楚。我们还讨论了黑色素瘤侵袭性的机制，这是它最有害的特征之一。C-MYC与肿瘤细胞的侵袭性诱导有关，尽管其机制尚不清楚。在过去的支持周期中，我们证实了C-MYC在促进黑色素瘤侵袭中的作用。此外，我们已经确定了参与核苷酸代谢的限速酶的先前未知的功能。我们发现一些这样的酶（由c - myc依赖基因编码）抑制衰老样表型，而其他酶则调节黑色素瘤细胞的侵袭性。本研究将建立c - myc依赖性核苷酸生物合成控制黑色素细胞OIS和黑色素瘤细胞侵袭性的机制。我们的发现具有广泛的科学吸引力，因为OIS的抑制是包括黑色素瘤在内的肿瘤发生的先决条件，而侵袭性是转移发展的关键条件，而转移是癌症最有害的阶段。黑色素瘤研究领域需要与疾病进展的特定阶段相关的可靠标志物。我们的初步数据表明，C-MYC可能是原发性黑色素瘤患者总生存（OS）的独立预后因素。因此，我们将单独确定C-MYC的预后价值，并与几个C-MYC靶点联合用于原发性黑色素瘤和淋巴结性黑色素瘤转移患者的预后价值。

DESCRIPTION (provided by applicant): Malignant melanoma is one of the most aggressive types of human cancer. Its ability to metastasize makes melanoma extremely difficult to cure, and consequently, the median survival of patients with metastatic melanoma is only 8.5 months. The molecular mechanisms underlying melanoma development are not well understood, and reliable markers associated with specific stages of melanoma progression are yet to be determined. Activating amino acid substitutions in oncoproteins BRAF (V600E) and NRAS (Q61R) have been found in approximately 60% and 20% of melanomas, respectively. Intriguingly, the same mutations were found at even higher frequencies in samples from benign human nevi (aggregation of normal melanocytes). In cultured normal human melanocytes, BRAFV600E or NRASQ61R induce senescence phenotypes that are virtually identical to those observed in nevi. Thus, melanomas originating from nevi must have developed mechanisms to overcome oncogene-induced senescence (OIS), but the nature of such mechanisms is largely unknown. We have recently demonstrated that unlike mouse or human fibroblasts, depletion of p53 or p16INK4A tumor suppressors is not sufficient to overcome OIS in human melanocytes. Instead, we have demonstrated that ectopic expression of oncoprotein C-MYC significantly suppressed BRAFV600E- and, less efficiently, NRASQ61R- induced senescence in these cells. Moreover, we demonstrated for the first time that depletion of C-MYC in human metastatic melanoma cells re-activated dormant BRAFV600E- or NRASQ61-specific senescence programs, thus indicating that C-MYC is required for continuous suppression of OIS during melanoma progression. C-MYC is a transcription factor that regulates the expression of multiple genes involved in many cellular processes. It is overexpressed in the vast majority of human malignancies, including melanoma. The mechanisms by which C-MYC suppresses OIS or RS in normal human melanocytes or keeps senescence programs dormant in human melanoma cells remain unknown. We also address the mechanism underlying melanoma invasiveness, one of its most detrimental features. C-MYC has been implicated in the induction of invasiveness in tumor cells, although the mechanisms are not known. In the past cycle of support, we confirmed the role of C-MYC in promoting melanoma invasiveness. Also, we have identified previously unknown functions for the rate-limiting enzymes involved in the metabolism of nucleotides. We found that several of such enzymes (encoded by C-MYC-dependent genes) suppress senescence-like phenotypes while others regulate melanoma cell invasiveness. The proposed research will establish the mechanisms by which C-MYC-dependent nucleotide biosynthesis controls OIS in melanocytic cells and invasiveness in melanoma cells. Our findings have broad scientific appeal since the suppression of OIS is a prerequisite for tumorigenesis including melanomagenesis, and invasiveness is a key condition for the development of metastases which is the most detrimental stage of cancer. The field of melanoma research is in need of reliable markers associated with specific stages of the disease progression. Our preliminary data indicate that C-MYC is a likely independent prognostic factor for overall survival (OS) in primary melanoma patients. Therefore, we will determine OS prognostic values of C- MYC separately and in conjunction with several C-MYC targets for patients with primary melanomas and nodal melanoma metastases. PUBLIC HEALTH RELEVANCE: Metastatic melanoma is one of the most aggressive types of human cancer. Despite significant progress made in recent years, the molecular mechanisms of the disease and molecular markers associated with melanoma stages remain largely unknown. Our proposed research will discover new mechanisms underlying melanoma progression, new targets for melanoma therapy, and new prognostic factors for overall survival in melanoma patients.