Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism.
Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism.
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Palladin 突变导致家族性胰腺癌，并提出了一种新的癌症机制。
DOI：
10.1371/journal.pmed.0030516
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发表时间：
2006-12
期刊：
影响因子：
15.8
通讯作者：
Brentnall, Teresa A.
中科院分区：
文献类型：
--
作者：
Pogue-Geile, Kay L.;Chen, Ru;Bronner, Mary P.;Crnogorac-Jurcevic, Tatjana;Moyes, Kara White;Dowen, Sally;Otey, Carol A.;Crispin, David A.;George, Ryan D.;Whitcomb, David C.;Brentnall, Teresa A.
胰腺癌是一种致命的疾病。导致疾病遗传形式的突变基因的发现可能有助于揭示肿瘤发生的机制。此前，我们将家族性胰腺癌的易感位点分离到染色体位置 4q32-34。在这项研究中，我们的目标是发现 4q32 上的家族性胰腺癌基因的身份并确定该基因的功能。影响胰腺癌易感性的候选染色体区域的定制微阵列揭示了帕拉丁（PALD）的最大表达变化，帕拉丁是一种编码控制细胞形状和运动的细胞骨架成分的基因。所有受影响的家族成员都追踪到了一个高度保守区域的突变，导致脯氨酸（疏水性）变为丝氨酸（亲水性）氨基酸变化（P239S），而在未受影响的成员中则不存在这种突变。该突变变化不是已知的单核苷酸多态性。通过定量 RT-PCR 测量，Palladin RNA 在家族性和散发性疾病的癌前不典型增生和胰腺癌组织中过度表达。将野生型和 P239S 突变 Palladin 基因构建体转染 HeLa 细胞显示出明显的表型效应：表达 P239S Palladin 的细胞表现出细胞骨架变化、肌动蛋白束组装异常和迁移能力增强。这些观察结果表明，家族性胰腺癌中异常palladin基因的存在和散发性胰腺癌中palladin蛋白的过度表达导致胰腺癌的细胞骨架变化，并可能是肿瘤强大的侵袭和迁移能力的原因或促成因素。家族性胰腺癌中异常帕拉丁的存在及其在散发性胰腺癌中的过度表达会导致细胞骨架的变化，并可能导致肿瘤的侵袭和迁移能力。胰腺癌是美国癌症相关死亡的主要原因。由于胰腺癌在早期阶段几乎不会引起任何症状，因此在其扩散（转移）到全身之前很少被发现。胰腺肿瘤偶尔可以通过手术切除，但通常的治疗方法是放疗或化疗，而这些都无法治愈；大多数患者在诊断后一年内死亡。与其他癌症一样，胰腺肿瘤中的细胞发生了基因变化（突变），使它们能够不受控制地分裂（正常细胞分裂只是为了修复受损组织）。其他突变会改变细胞的形状，并允许它们迁移到（入侵）身体的其他区域。这些突变通常是随机发生的——人体内的细胞受到化学物质和其他可能损害其 DNA 的物质的轰击——并导致“散发性”胰腺癌。但有些人继承了突变基因，增加了患胰腺癌的易感性。这些人很容易被认出，因为胰腺癌在他们的家庭中比在一般人群中更常见。家族性胰腺癌中突变基因的鉴定可能有助于了解遗传性和散发性癌症如何在胰腺中发生。这些信息可能会提出比目前更早检测胰腺癌的方法，并可能确定这种致命疾病的新治疗靶点。进行这项研究的研究人员之前的工作将导致遗传性胰腺癌的基因定位于胰腺癌非常常见的家族（X家族）中4号染色体的一个小区域。在这项研究中，研究人员确定了该区域的哪些基因可能与 X 家族的胰腺癌易感性有关。研究人员制作了 X 家族中与胰腺癌相关的染色体区域中 243 个基因的 DNA 微阵列（带有 DNA 序列的小芯片）。他们用它来检查 X 家族成员的发育不良胰腺组织（胰腺发育不良是癌症之前的癌前病变）、正常胰腺组织和样本中的基因表达。来自散发性胰腺癌。 X家族组织和散发性癌症中过度表达程度最高（与正常组织相比）的基因编码了一种称为palladin的蛋白质。 Palladin 是细胞骨架（一种有助于控制细胞形状和运动的结构）的组成部分，它组织其他细胞骨架成分。接下来，研究人员对一组独立的正常和癌性胰腺样本以及取自 X 家族成员和遗传性胰腺癌但不属于 X 家族的人的癌前胰腺组织中 Palladin RNA 的表达进行了定量。该分析表明，palladin 在散发性和遗传性胰腺癌发展的早期过度表达。随后对 Palladin 基因进行测序，发现 Palladin 存在突变，这种突变存在于患有胰腺癌或癌前病变的 X 家族成员中，但未受影响的成员中则没有。这种特定的突变可能会影响 palladin 与另一种称为 α-肌动蛋白 的细胞骨架蛋白的相互作用，但在散发性癌症中并未发现这种突变，尽管许多散发性癌细胞系除 palladin 蛋白外还存在 α-肌动蛋白蛋白的异常表达。最后，研究人员表明，将突变的帕拉丁引入实验室生长的人类细胞系中，可以提高其迁移率并破坏其细胞骨架。这些结果强烈表明突变的帕拉丁参与了家族性胰腺癌的发生。由于基因往往会在群体中遗传，因此附近基因的突变仍有可能导致 X 家族中胰腺癌易感性增加。然而，数据显示帕拉丁在散发性肿瘤中过度表达，以及引入突变基因后实验室中细胞行为的改变使这种情况不太可能发生。为了证明 Palladin 与胰腺癌有关，现在必须在其他家族病例中鉴定出 Palladin 突变，并且必须解释散发性癌症中 Palladin 的过度表达。然而，这里的结果提供了一个有趣的视角，让我们了解胰腺和可能的其他组织中癌症发展的潜在新机制，其中帕拉丁功能或表达（或与其相关的蛋白质）的异常驱动了癌细胞特征的细胞迁移、形状和大小的一些变化。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0030516 美国国家癌症研究所，为患者和健康专业人员提供的有关胰腺癌的信息 MedlinePlus 胰腺癌百科全书条目 英国癌症研究中心，为患者提供的有关胰腺癌的信息 约翰·霍普金斯大学，有关胰腺癌的信息，包括家族性癌症的详细信息 CancerQuest，埃默里大学提供的有关癌症如何发展的信息
Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32–34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene. A customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate. These observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities. The presence of abnormalpalladin in familial pancreatic cancer and its overexpression in sporadic pancreatic cancer leads to cytoskeletal changes and may be responsible for the tumor's invasive and migratory abilities. Pancreatic cancer is a leading cause of cancer-related death in the US. Because it causes few symptoms in its early stages, pancreatic cancer is rarely detected until it has spread (metastasized) around the body. Pancreatic tumors can occasionally be removed surgically but the usual treatment is radio- or chemotherapy, and neither of these is curative; most patients die within a year of diagnosis. As in other cancers, the cells in pancreatic tumors have acquired genetic changes (mutations) that allow them to divide uncontrollably (normal cells divide only to repair damaged tissue). Other mutations alter the shape of the cells and allow them to migrate into (invade) other areas of the body. These mutations usually arise randomly—the cells in the human body are bombarded by chemicals and other agents that can damage their DNA—and cause “sporadic” pancreatic cancer. But some people inherit mutated genes that increase their susceptibility to pancreatic cancer. These people are recognizable because pancreatic cancer is more common in their families than in the general population. The identification of the genes that are mutated in familial pancreatic cancer might provide insights into how both inherited and sporadic cancer develops in the pancreas. Such information could suggest ways to detect pancreatic cancers earlier than is currently possible and could identify new therapeutic targets for this deadly disease. Previous work by the researchers who did this study localized a gene responsible for inherited pancreatic cancer to a small region of Chromosome 4 in a family in which pancreatic cancer is very common (Family X). In this study, the researchers identified which of the genes in this region is likely to be responsible for the susceptibility to pancreatic cancer of Family X. The researchers made a DNA microarray (a small chip spotted with DNA sequences) of the 243 genes in the chromosomal region linked to pancreatic cancer in Family X. They used this to examine gene expression in dysplastic pancreatic tissue from a Family X member (pancreatic dysplasia is a precancerous lesion that precedes cancer), in normal pancreatic tissue, and in samples from sporadic pancreatic cancers. The most highly overexpressed (compared to normal tissue) gene in both the Family X tissue and the sporadic cancers encoded a protein called palladin. Palladin is a component of the cytoskeleton (a structure that helps to control cell shape and motility) and it organizes other cytoskeletal components. Next, the researchers quantified the expression of palladin RNA in an independent set of normal and cancerous pancreatic samples, and in precancerous pancreatic tissue taken from Family X members and from people who inherit pancreatic cancer but who were not in Family X. This analysis indicated that palladin was overexpressed early in sporadic and inherited pancreatic cancer development. Sequencing of the palladin gene then uncovered a mutation in palladin that was present in Family X members with pancreatic cancer or precancerous lesions but not in unaffected members. This specific mutation, which probably affects palladin's interaction with another cytoskeletal protein called alpha-actinin, was not found in sporadic cancers although many sporadic cancer cell lines had abnormal expression of alpha-actinin protein in addition to palladin protein. Finally, the researchers showed that the introduction of mutated palladin into a human cell line growing in the laboratory increased its migration rate and disrupted its cytoskeleton. These results strongly suggest that mutated palladin is involved in the development of familial pancreatic cancer. Because genes tend to be inherited in groups, there is still chance that a mutation in a nearby gene could be responsible for the increased susceptibility to pancreatic cancer in Family X. However, the data showing palladin overexpression in sporadic tumors and alterations of cell behavior in the laboratory after introduction of the mutated gene make this unlikely. To prove the involvement of palladin in pancreatic cancer, palladin mutations must now be identified in other familial cases and the overexpression of palladin in sporadic cancers must be explained. The results here nevertheless provide an intriguing glimpse into a potential new mechanism for cancer development in the pancreas and possibly other tissues, one in which abnormalities in palladin function or expression (or in the proteins with which it associates) drive some of the changes in cell migration, shape, and size that characterize cancer cells. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030516 US National Cancer Institute, information on pancreatic cancer for patients and health professionals MedlinePlus encyclopedia entry on pancreatic carcinoma Cancer Research UK, information for patients about pancreatic cancer Johns Hopkins University, information on pancreatic cancer that includes details on familial cancer CancerQuest, information provided by Emory University about how cancer develops
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影响因子：
4
作者：
EVANS, JP;BURKE, W;BYRD, DR
通讯作者：
BYRD, DR
影响因子：
50.5
作者：
Hruban, RH;Petersen, GM;Kern, SE
通讯作者：
Kern, SE
DOI：
10.1073/pnas.94.3.849
发表时间：
1997-02-04
影响因子：
11.1
作者：
Maniotis, AJ;Chen, CS;Ingber, DE
通讯作者：
Ingber, DE
影响因子：
3.5
作者：
Rönty, M;Taivainen, A;Carpén, O
通讯作者：
Carpén, O
影响因子：
2.9
作者：
BenZeev, A
通讯作者：
BenZeev, A