蛋白连接肝癌与肥胖，酒精中毒，和肝炎

StephenW

Protein links liver cancer with obesity, alcoholism, and hepatitis

Obesity, alcoholism, and chronic hepatitis all increase the risk of getting liver cancer, which is the third leading cause of cancer death worldwide. Obesity in particular is driving a significant increase in liver cancer in the United States. These three health problems also increase cellular stress in the liver, but until now it has not been clear if there is a direct biological link between cellular stress and the development of liver cancer.

In a new study, University of Iowa researchers have identified an unexpected molecular link between liver cancer, cellular stress, and these health problems that increase the risk of developing this cancer.

The study, published Dec. 19 in the journal PLOS Genetics, shows that a protein called CHOP, which had previously been thought to generally protect against cancer, actually promotes liver cancer in mice and may do the same in humans.

"Obesity, alcoholism, and viral hepatitis are all known independently to cause cellular stress and to induce expression of CHOP," says Thomas Rutkowski, Ph.D., assistant professor of anatomy and cell biology in the UI Carver College of Medicine and senior study author. "So this finding suggests a biological pathway that links those 'upstream' health problems to liver cancer at the end."

CHOP is a transcription factor that is produced when cells experience certain kinds of stress. It is known to promote cell death, or apoptosis. Usually, factors that promote cell death protect against cancer by causing damaged cells to die.

The study shows that, despite its role in cell death, CHOP actually is elevated in liver tumor cells in mice. Furthermore, mice without CHOP are partially protected from liver cancer, developing fewer and smaller tumors than the normal mice in response to liver cancer-causing drugs. The mice without CHOP also had less liver scarring and inflammation than mice with the protein.

Tissue samples from human patients show that CHOP also is elevated in human liver tumors compared to surrounding non-tumor tissue from the same patients.

"We turned out to be completely wrong about CHOP. We found that it contributes to the development of liver cancer in mice and is associated with liver cancer in humans," Rutkowski says. "CHOP is indeed killing cells, just as we thought it would, but we think the consequence of this killing is not the prevention of tumors, but instead the stimulation of inflammatory signals in the liver that cause excessive proliferation of other cells," he explains.

Rutkowski notes that although this proposed mechanism is not proven yet, it is consistent with what is known about the role of CHOP.

Collaboration was critical to the success of the study, Rutkowski adds. Postdoctoral researcher Diane McCabe in his lab performed most of the experiments, and McCabe and Rutkowski worked closely with cancer biology expert Adam Dupuy, Ph.D., UI associate professor of anatomy and cell biology, and his graduate student Jesse Riordan. Another collaboration with Michael Icardi, M.D., UI associate professor of pathology, gave Rutkowski access to liver tissue samples from patients that allowed the team to show the association between elevated CHOP and human liver cancer.

Having implicated CHOP as a contributing factor in liver cancers associated with obesity, alcoholism, and hepatitis, Rutkowski next wants to learn whether CHOP acts early in the process of tumor formation or if it plays a role in helping established tumors to grow. He also is interested in identifying the other proteins that partner with CHOP to promote liver cancer.

"This discovery opens up an avenue into a new pathway that promotes liver cancer," he says. "Once we know what those other genes are that interact with CHOP, then maybe we can find a 'druggable' target molecule. The hope is that down the line scientists will be able to convert that finding into something therapeutically useful for patients.

"Federal funding is the backbone of this kind of research, which has the potential to make unexpected discoveries that, in this case, could help improve cancer treatment," he adds.

StephenW

蛋白连接肝癌与肥胖，酒精中毒，和肝炎

肥胖，酗酒，慢性肝炎都会增加罹患肝癌，这是全世界癌症死亡的第三大原因的风险。肥胖尤其是驾驶在美国在肝癌显著增加。这三个健康问题也增加了肝细胞压力，但是到现在为止它一直没有明确是否存在细胞应激和肝癌的发展之间有直接的生物学联系。

在一项新研究，爱荷华大学的研究人员已经确定了肝癌，细胞应激，而这些，便是增加患这种癌症的风险，健康问题之间的一个意想不到的分子联系。

这项研究，在杂志PLoS遗传学发布的12月19日，显示了一个名为CHOP蛋白，它此前被​​认为是一般预防癌症，真正促进肝癌小鼠和人类中也可以这样做。

“肥胖，酗酒，和病毒性肝炎是所有已知的独立引起细胞应激和诱导CHOP的表达， ”托马斯·卢特考斯基博士，解剖学和细胞生物学助理教授在医学UI Carver医学院和高级研究说作者。 “因此，这一发现表明一个生物途径，链接这些”上游“的健康问题，以肝癌底。 ”

CHOP ]是产生当细胞经历若干种应力的一种转录因子。它是已知的，以促进细胞死亡或凋亡。通常情况下，促进细胞死亡的因素，防止癌症通过使受损的细胞死亡。

研究表明，尽管它在细胞死亡的作用，实际上CHOP升高肝肿瘤细胞在小鼠体内。此外，小鼠不CHOP被部分保护，肝癌，显影比正常小鼠响应于肝脏致癌药物更少和更小的肿瘤。不砍老鼠也有少肝脏疤痕和发炎的小鼠比用蛋白质。

从人类患者的组织样本显示， CHOP也升高在人类肝肿瘤相比，来自同一患者的周围的非肿瘤组织。

“我们原来是完全错误的关于CHOP方案。我们发现，它有助于肝癌小鼠的发展，并与在人类肝癌有关，”卢特考斯基说。 “ CHOP确实杀死细胞，就像我们想的那样，但我们认为这种杀人的后果是无法预防的肿瘤，但在肝脏炎症信号，导致其他细胞的过度增殖，而不是刺激， ”他解释说。

卢特考斯基指出，虽然这个建议的机制尚未证实的是，它与我们所了解的CHOP的作用是一致的。

合作是这项研究的成功至关重要，卢特考斯基补充道。博士后研究员戴安娜麦凯布在他的实验室进行大部分的实验，并麦凯布和卢特考斯基密切合作，与癌症生物学专家亚当·杜佩，博士，解剖学和细胞生物学的UI副教授，和他的研究生杰西·赖尔登。与迈克尔Icardi ，医学博士，病理学UI副教授另一个协作，卢特考斯基给病人，让球队呈现出较高的CHOP方案和肝癌之间的关系进入肝组织标本。

有牵连CHOP如肥胖，酒精中毒，和肝炎相关的肝癌症的一个因素，卢特考斯基接下来想学习CHOP是否在肿瘤形成过程的早期起作用，或者如果它在帮助建立的肿瘤生长中起着一定的作用。他还有意物色其他蛋白质与CHOP合作伙伴，以促进肝癌。

“这一发现开辟了一个途径到一个新的途径，促进肝癌， ”他说。 “一旦我们知道这些其他基因是与CHOP交互，那么也许我们可以找到一个”成药“的目标分子。希望是向下行的科学家将能够转换，寻找到的东西对患者的治疗是有用的。

“联邦资助是这方面的研究，其中有做出意想不到的发现是，在这种情况下，可能有助于提高癌症治疗的潜在的中坚力量， ”他补充道。