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《自然》重磅:肝癌大突破!拉斯克獎大牛發現全新抑癌蛋白,有望突破肝癌診療的瓶頸 | 科學大發現
27/03/2018

奇點網 / Medicalxpress

《自然》重磅:肝癌大突破!拉斯克獎大牛發現全新抑癌蛋白,有望突破肝癌診療的瓶頸 | 科學大發現

 

在癌症這個殺手家族中,肝癌可以排得上全球老二了。在我國,肝癌也是高發癌種,而且由於其發病隱匿、疾病進展快,患者的預後極不樂觀,新的診療方法迫在眉睫。

 

本周的《自然》雜誌上刊登了一項來自瑞士巴塞爾大學的研究,Michael N. Hall帶領的研究團隊發現了一種全新的抑癌蛋白LHPP,這種蛋白的喪失促進了腫瘤的生長,增加LHPP表達則能夠有效抑制癌細胞增殖並阻止肝功能損傷[1]!除此之外,LHPP水準也與疾病負擔和患者預後有關,研究者認為可以作為診斷和預後的生物指標。

 

 

本項研究的通訊作者Michael N. Hall, 也是雷帕黴素靶蛋白(TOR)信號通路的發現者

 

 

在原發性肝癌中,90%屬於肝細胞癌(HCC)[2],而50%的肝細胞癌又都涉及mTOR信號通路[3]。研究者通過特異性敲除小鼠的PTEN、TSC1啟動mTOR通路,改造小鼠在6周大時出現肝腫大,20周則完全發展為肝細胞癌。經過對小鼠肝臟的分子特徵分析,這種小鼠肝癌特徵幾乎與人類肝癌特徵一樣[4,5]。研究者把這種小鼠叫做L-dKO小鼠。

 

 

L-dKO小鼠(右)會自發生長肝細胞癌

 

 

 

隨後,研究者對20周大的L-dKO小鼠的腫瘤組織和正常的健康小鼠肝組織進行了蛋白質組學分析,涉及4500種蛋白。功夫不負苦心人,研究者最終篩選出了一種差異很大的蛋白——LHPP。這種蛋白在健康組織中可以正常表達,在癌組織中卻幾乎不存在。

 

經過免疫組化方法驗證,LHPP是一種組氨酸磷酸酶,也就是從蛋白中解除磷酸基團的酶。此前發現了唯二兩種在哺乳動物中相關的酶是NME1、NME2(也稱為NDPKA、NDPKB)。這是兩種磷酸激酶,相應地,在肝癌組織中表達有所升高。

 

研究者分別對不同癌症發展階段的小鼠進行了蛋白表達分析,發現隨著癌症的發展,LHPP表達逐漸降低、乃至消失,同時NME1、NME2則與mTOR一同保持著很高的水準。而腫瘤周邊的非癌組織中,LHPP水準正常。另一方面,癌組織的磷酸化水準則整體升高了。

 

 

 

癌組織和非癌組織中各蛋白水準的比較

 

 

 

但是這也不能說明LHPP在肝癌發展中到底處於怎樣的地位,到底是因是果?於是研究者利用腺病毒轉染,重新將LHPP基因導入了L-dKO小鼠中。在小鼠8周大時,通過尾靜脈注射,確保小鼠中LHPP蛋白會過量表達。

 

在小鼠20周大時,研究者對小鼠肝臟進行了檢測,結果很令人驚訝!導入了LHPP基因的小鼠肝臟腫瘤數量、大小都大大降低!研究者還對小鼠的丙氨酸氨基轉移酶(ALT)、天冬氨酸氨基轉移酶(AST)、乳酸鹽脫氫酶(LDH)等肝損傷特徵指標進行了檢測,結果也顯示,LHPP蛋白對肝功能有良好的保護作用。

 

 

這足以說明LHPP是一種新的抑癌蛋白!

 

轉染LHPP的小鼠明顯腫瘤數量較少,體積也較小

 

 

 

小鼠實驗畢竟是小鼠實驗,LHPP的抑癌作用在人類中是否也存在呢?研究者分析了20例肝細胞癌患者的組織樣本,並和它們自己的非癌組織樣本進行對比,發現癌組織中的LHPP水準有了大幅度的下降。

 

在小鼠實驗中,LHPP的水準既然會隨癌症發展變化,那麼是不是說明LHPP水準可能與臨床指標有關呢?對前人公佈的研究資料[6]進行二次分析,研究者發現,與小鼠研究一致,低LHPP表達與更重的疾病負擔、更短的生存期有關!低LHPP表達患者的中位生存期足足減少了近兩年!

 

 

 

無病生存期(上)和整體生存期(下)

 

 

 

研究者也分析了癌症基因圖譜(TCGA)和國際癌症基因組聯盟(ICGC)的資料,包括49種LHPP突變,其中24.5%發現於食管癌、頭頸癌、胃癌、膀胱癌、乳腺癌、皮膚癌、肝癌、肺癌、胰腺癌等多種癌症。這些突變的形式均屬於功能缺失型突變。這項資料也再次說明LHPP是一種抑癌基因[7]。

 

除此以外,也曾有研究者發現LHPP與口腔癌、咽喉癌、急性淋巴細胞白血病有關[8,9]。

 

以上研究資料表明,LHPP是一種新發現的抑癌蛋白,它的缺失會導致整體蛋白組氨酸磷酸化增加,並進一步促進癌症的發展和其他疾病。

 

至於為什麼組氨酸磷酸化會與癌症有關呢?研究者檢測的組氨酸磷酸化蛋白質包括關鍵的DNA複製因數、p53抑制劑、以及會誘發突變的胞苷脫氨酶等等與癌症相關的蛋白。缺乏LHPP導致的整體磷酸化增加,很有可能就啟動了有重要功能的通路,自然很容易導致癌症發生了。

 

 

 

参考资料:

[1] https://www.nature.com/articles/nature26140

[2] Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2,16018–16023 (2016).

[3] Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47,505–511 (2015).

[4] Kenerson, H. L. et al. Akt and mTORC1 have different roles during liver tumorigenesis in mice. Gastroenterology 144, 1055–1065 (2013).

[5] Guri, Y. et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell 32, 807–823 (2017).

[6] Makowska, Z. et al. Gene expression analysis of biopsy samples reveals critical limitations of transcriptome-based molecular classifcations of hepatocellular carcinoma. J. Pathol. Clin. Res. 2, 80–92 (2016).

[7] Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558(2013).

[8] Vijayakrishnan, J. et al. A genome-wide association study identifes risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1. Leukemia 31, 573–579 (2017).

[9] Lesseur, C. et al. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat. Genet. 48, 1544–1550 (2016).

 

 

 

 

Researchers discover new anti-cancer protein

March 21, 2018, University of Basel

 

 

Scanning electron microscopy image of cancer cells. Credit: University of Basel, Biozentrum/Swiss Nanoscience Institute

 

 

An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in Nature that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.

 
 

The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled in Switzerland. Hepatocellular carcinoma is usually diagnosed at a very late stage when the liver is already severely damaged and hence overall prognosis is poor. Detection of the anti-cancer protein LHPP as a biomarker may allow clinicians to provide better treatment options.

 

 

New anti-cancer protein LHPP

 

Liver tumors develop from mutated cells that grow and proliferate uncontrollably. Anti-cancer proteins, so-called tumor suppressors, prevent uncontrolled cell growth. Tumor suppressors are often defective in cancer cells. The researchers led by Prof. Michael N. Hall, Biozentrum of the University of Basel, have now discovered a new, so far unknown tumor suppressor, the protein LHPP. In their study, they show that the loss of LHPP promotes tumor growth and reduces the chance of survival of cancer patients. LHPP could potentially be used as a prognostic biomarker.

 

The researchers generated a mouse model for hepatocellular carcinoma by activating mTOR signaling specifically in the liver. They analyzed a total of more than 4,000 proteins, comparing them in healthy and tumor tissue. An enzyme emerged as the top favorite: the histidine phosphatase LHPP. "It is striking that LHPP is present in healthy tissue and completely absent in tumor tissue," says first author Sravanth Hindupur. Re-introduction of the genetic information for LHPP by the researchers prevents the formation of tumors and maintains liver function.

 

 

Loss of LHPP in cancer patients

 

"Similar to the mouse model, we also saw a striking decrease in LHPP levels in tumors of patients with liver cancer," says Hindupur. Additionally, both disease severity and life expectancy correlate with LHPP levels. With complete loss of the tumor suppressor, cancer patients die on average two years earlier. LHPP is useful as a biomarker to classify tumors. 

 

 

Phosphorylation important for tumorigenesis

 

LHPP is a phosphatase that removes histidine-linked phosphate groups from proteins. Like all amino acids, histidine is a basic component of proteins. Histidine phosphorylation of proteins has been poorly investigated due to the lack of suitable tools. "Tony Hunter, from the Salk Institute in the USA, has provided us with new tools to analyze histidine phosphorylation. We have now been able to visualize a whole new layer of complexity in tumor formation," says Hindupur.

 

Due to the absence of LHPP, global protein histidine phosphorylation is increased, which can lead to activation of several important functions and uncontrolled cell proliferation. This absence promotes the growth of tumors via increasing histidine-phosphorylated proteins. The tumor suppressor LHPP may also play a role in the development of other cancers.

 

 

More information: Sravanth K. Hindupur et al, The protein histidine phosphatase LHPP is a tumour suppressor, Nature (2018). DOI: 10.1038/nature26140

 

 

 

文章來自: 奇點網 / Medicalxpress

中: https://mp.weixin.qq.com/s/kaigcoHe-pZJSDSANKRO3A

Enghttps://medicalxpress.com/news/2018-03-anti-cancer-protein.html

 

 

 

 

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