Investigation of control of pRB and cell transformation by a long non-coding RNA

黑色素瘤是一种被称为黑素细胞的色素产生细胞的癌症，最常见的是皮肤。黑色素瘤是英国第六种最常见的癌症，晚期黑色素瘤的预后仍然非常差。2016年，英国约有13,300人将被诊断为黑色素瘤。按照目前的速度，其中大约2100人将死于这种疾病。因此，有必要更好地了解这种疾病，以最终促进更好的治疗。值得注意的是，大多数人携带最早可检测到的皮肤损伤作为黑色素瘤的先兆，表现为良性的人类痣或葡萄胎。葡萄胎通常携带一种已知的导致黑色素瘤的基因变化，要么是激活的NRAS，要么是BRAF癌基因。然而，葡萄胎很少发展成黑色素瘤，因为携带癌基因的黑素细胞通过一种称为细胞衰老的过程阻止了增殖。因此，更好地了解黑素细胞的衰老有助于了解人体对黑色素瘤的天然防御。最终，这可能会被运用到治疗中。视网膜母细胞瘤肿瘤抑制因子(PRB)是细胞衰老和防止肿瘤形成的关键分子之一。顾名思义，这种分子最初是通过其预防视网膜母细胞瘤的能力被发现的，视网膜母细胞瘤是一种眼癌。然而，pRb也有助于抑制黑色素瘤和许多其他癌症，部分是通过激活细胞衰老。因此，了解PRB的控制是很重要的。我们发现了另一种名为LNC98的分子，它是细胞产生PRB所必需的。这反过来表明LNC98可能会抑制黑色素瘤的形成。与这一观点一致，我们发现LNC98在一些人类黑色素瘤中是失活的，这可能是它们不受限制地生长和增殖的原因。在这项研究中，我们将研究LNC98促进细胞内pRb产生的分子机制，并探讨LNC98在抑制黑色素瘤中的作用。这些研究的完成将为管理和治疗黑色素瘤提供新的治疗途径。

Melanoma is a cancer of pigment producing cells called melanocytes, most often in the skin. Melanoma is the 6th most common cancer in the UK and advanced melanoma still has a very poor prognosis (www.cancerresearchuk.org). In 2016, approximately 13,300 people in the UK will be diagnosed with melanoma. At current rates, approximately 2,100 of these will die from the disease. Thus, there is a need for a better understanding of this disease to ultimately facilitate better cures. Remarkably, most people carry the earliest detectable skin lesions as precursors to melanoma, in the form of benign human nevi or moles. Moles typically carry one of the genetic alterations known to drive melanoma, either an activated NRAS or BRAF oncogene. However, moles only very rarely progress to melanoma because the melanocytes harboring the oncogene are prevented from proliferating by a process called cell senescence. Consequently, a better understanding of senescence in melanocytes can aid in understanding the body's natural defences to melanoma. Eventually, this might be harnessed in therapies. One molecule critical for cell senescence and preventing tumor formation is the retinoblastoma tumor suppressor (pRB). As its names suggests, this molecule was first discovered through its ability to prevent retinoblastoma, a cancer of the eye. However, pRB also contributes to suppression of melanoma and many other cancers, in part through activation of cell senescence. Thus, it is important to understand control of pRB. We have discovered another molecule, called LNC98, which is required for cells to produce pRB. This in turn suggests that LNC98 might suppress melanoma formation. Consistent with this idea, we have found that LNC98 is inactivated in some human melanomas, perhaps accounting for their unrestrained growth and proliferation. In this study, we will investigate the molecular mechanism by which LNC98 promotes production of pRB in cells and investigate the role of LNC98 in suppression of melanoma. Completion of these studies should provide new therapeutic avenues to manage and treat melanoma.