Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis.
Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis.
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DOI：
10.1111/cas.14895
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发表时间：
2021-06
期刊：
影响因子：
5.7
通讯作者：
Shima H
中科院分区：
文献类型：
--
作者：
Kanazawa K;Kishimoto K;Nomura M;Kurosawa K;Kato H;Inoue Y;Miura K;Fukui K;Yamashita Y;Sato I;Tsuji H;Watanabe T;Tanaka T;Yasuda J;Tanuma N;Shima H
根据TCGA数据库，PPP 6C（编码磷酸酶PP 6）的突变在c. 10%的肿瘤来自黑色素瘤患者，其中它们与BRAF和NRAS突变共存。为了评估PP 6在黑色素瘤致癌作用中的功能，我们产生了小鼠，其中我们可以特异性诱导BRAF（V600 E）表达并删除黑色素细胞中的Ppp 6c。在这些小鼠中，UVB照射后的黑色素瘤易感性表现出以下模式：Ppp 6c半缺陷型（杂合型）> Ppp 6c野生型> Ppp 6c缺陷型（纯合型）肿瘤类型。对Ppp 6c杂合型和野生型黑色素瘤肿瘤的下一代测序显示，所有肿瘤均携带Trp 53突变。然而，与Ppp 6c野生型肿瘤相比，Ppp 6c杂合子肿瘤显示出更高的Signature 1（有丝分裂/有丝分裂时钟）突变指数，表明细胞分裂增加。对来自Ppp 6c杂合或野生型黑色素瘤组织的细胞系的分析表明，两者都在裸鼠中形成肿瘤，但与野生型细胞系相比，Ppp 6c杂合肿瘤生长得更快。在Ppp 6c杂合系中通过siRNA敲低Ppp 6c促进了基因组损伤的积累，并且相对于siRNA对照增强了细胞凋亡。我们得出结论，在BRAF（V600 E）表达和UV诱导的Trp 53突变的存在下，Ppp 6c单倍不足促进肿瘤发生。为了评估PP 6在黑色素瘤致癌作用中的功能，我们产生了小鼠，其中我们可以特异性诱导BRAF（V600 E）表达并删除黑色素细胞中的Ppp 6c。使用这些小鼠，我们观察到黑色素瘤对UVB照射的敏感性在Ppp 6c半缺陷（杂合）> Ppp 6c野生型> Ppp 6c缺陷（纯合）肿瘤类型中最大，按此顺序。在BRAF（V600 E）表达和UV诱导的Trp 53突变的存在下，Ppp 6c单倍不足促进肿瘤发生。
According to TCGA database, mutations in PPP6C (encoding phosphatase PP6) are found in c. 10% of tumors from melanoma patients, in which they coexist with BRAF and NRAS mutations. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF(V600E) expression and delete Ppp6c in melanocytes. In these mice, melanoma susceptibility following UVB irradiation exhibited the following pattern: Ppp6c semi‐deficient (heterozygous) > Ppp6c wild‐type > Ppp6c‐deficient (homozygous) tumor types. Next‐generation sequencing of Ppp6c heterozygous and wild‐type melanoma tumors revealed that all harbored Trp53 mutations. However, Ppp6c heterozygous tumors showed a higher Signature 1 (mitotic/mitotic clock) mutation index compared with Ppp6c wild‐type tumors, suggesting increased cell division. Analysis of cell lines derived from either Ppp6c heterozygous or wild‐type melanoma tissues showed that both formed tumors in nude mice, but Ppp6c heterozygous tumors grew faster compared with those from the wild‐type line. Ppp6c knockdown via siRNA in the Ppp6c heterozygous line promoted the accumulation of genomic damage and enhanced apoptosis relative to siRNA controls. We conclude that in the presence of BRAF(V600E) expression and UV‐induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF (V600E) expression and delete Ppp6c in melanocytes. Using these mice, we observed that melanoma susceptibility to UVB irradiation was greatest in Ppp6c semi‐deficient (heterozygous) > Ppp6c wild‐type > Ppp6c‐deficient (homozygous) tumor types, in that order. In the presence of BRAF (V600E) expression and UV‐induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
5.7
作者：
Kurosawa K;Inoue Y;Kakugawa Y;Yamashita Y;Kanazawa K;Kishimoto K;Nomura M;Momoi Y;Sato I;Chiba N;Suzuki M;Ogoh H;Yamada H;Miura K;Watanabe T;Tanuma N;Tachi M;Shima H
通讯作者：
Shima H
影响因子：
4.8
作者：
Hosing, Amol S.;Valerie, Nicholas C. K.;Larner, James M.
通讯作者：
Larner, James M.
影响因子：
1.7
作者：
Cheung, Wang L.;Patel, Rishi R.;Meehan, Shane A.
通讯作者：
Meehan, Shane A.