The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression.
The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression.
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肿瘤表达的CD38在肺腺癌进展中的内在作用和机制
DOI：
10.1038/s41419-021-03968-2
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发表时间：
2021-07-05
影响因子：
9
通讯作者：
Xiao-Feng Qin F
中科院分区：
文献类型：
--
作者：
Gao L;Liu Y;Du X;Ma S;Ge M;Tang H;Han C;Zhao X;Liu Y;Shao Y;Wu Z;Zhang L;Meng F;Xiao-Feng Qin F
最近有报道称，在多种鼠源和人源肿瘤细胞上表达的CD 38可响应于PD-L1抗体治疗而上调，这导致肿瘤浸润性CD 8 +T免疫细胞因腺苷产生增加而功能障碍。然而，肿瘤表达的CD 38在肿瘤形成和进展中的作用仍然是难以捉摸的。在本研究中，我们的目的是描绘肿瘤相关的CD 38在肺腺癌进展的分子和生化功能。我们的临床数据显示，肿瘤源性CD 38的上调与肺癌患者的生存率低相关。使用多种体外试验，我们发现肿瘤表达的CD 38的酶活性促进肺癌细胞迁移、增殖、集落形成和肿瘤发展。体内实验结果表明，抑制CD 38的酶活性或拮抗其酶产物，可产生与CD 38基因敲除或突变相似的抑制肿瘤增殖和转移的作用。在生化水平上，我们进一步证实了cADPR（CD 38的主要水解产物）在肺癌细胞中负责诱导TRPM 2铁通道开放，导致细胞内Ca 2+内流，进而导致NRF 2水平升高，而KEAP 1表达降低。这些结果表明，恶性肺癌细胞能够利用CD 38催化的cADPR促进肿瘤进展，阻断CD 38的酶活性可能是阻止肿瘤进展的重要策略。
It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.
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影响因子：
20.8
作者：
Chini CCS;Peclat TR;Warner GM;Kashyap S;Espindola-Netto JM;de Oliveira GC;Gomez LS;Hogan KA;Tarragó MG;Puranik AS;Agorrody G;Thompson KL;Dang K;Clarke S;Childs BG;Kanamori KS;Witte MA;Vidal P;Kirkland AL;De Cecco M;Chellappa K;McReynolds MR;Jankowski C;Tchkonia T;Kirkland JL;Sedivy JM;van Deursen JM;Baker DJ;van Schooten W;Rabinowitz JD;Baur JA;Chini EN
通讯作者：
Chini EN
影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
50.3
作者：
Berger AH;Brooks AN;Wu X;Shrestha Y;Chouinard C;Piccioni F;Bagul M;Kamburov A;Imielinski M;Hogstrom L;Zhu C;Yang X;Pantel S;Sakai R;Watson J;Kaplan N;Campbell JD;Singh S;Root DE;Narayan R;Natoli T;Lahr DL;Tirosh I;Tamayo P;Getz G;Wong B;Doench J;Subramanian A;Golub TR;Meyerson M;Boehm JS
通讯作者：
Boehm JS
影响因子：
64.5
作者：
Lignitto, Luca;LeBoeuf, Sarah E.;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
29
作者：
Chatterjee S;Daenthanasanmak A;Chakraborty P;Wyatt MW;Dhar P;Selvam SP;Fu J;Zhang J;Nguyen H;Kang I;Toth K;Al-Homrani M;Husain M;Beeson G;Ball L;Helke K;Husain S;Garrett-Mayer E;Hardiman G;Mehrotra M;Nishimura MI;Beeson CC;Bupp MG;Wu J;Ogretmen B;Paulos CM;Rathmell J;Yu XZ;Mehrotra S
通讯作者：
Mehrotra S