STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening.
STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening.
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DOI：
10.1186/s12929-018-0456-y
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发表时间：
2018-08-02
影响因子：
11
通讯作者：
Chang YF
中科院分区：
文献类型：
--
作者：
Cheng CC;Liao PN;Ho AS;Lim KH;Chang J;Su YW;Chen CG;Chiang YW;Yang BL;Lin HC;Chang YC;Chang CC;Chang YF
癌症干细胞在癌症治疗后能够进行细胞分裂，导致肿瘤进展和复发。针对癌症干细胞的抑制剂可能用于治疗有效地根除肿瘤。因此，本研究的目的是在表皮生长因子受体（EGFR）阳性的结直肠癌（CRC）细胞中识别维持癌干性的相关驱动基因，并发现针对这些基因的有效治疗药物。本研究以来源于HCT116和HT29细胞的egfr阳性肿瘤干细胞（CSLCs）作为体外诱导的研究模型。为了鉴定维持CSLCs的差异基因，先进行RNAseq分析，然后进行生物信息学分析。此外，一个包含172种靶向干细胞各种途径的治疗剂的小组被用来确定针对CSLCs的有效治疗方法。RNAseq分析显示，HCT116 CSLCs中分别有654个和840个基因显著上调和下调。在这些基因中，值得注意的是，血小板衍生生长因子A （PDGFA）和信号换能器和转录激活因子3 （STAT3）根据使用NetworkAnalyst分析的癌症途径是相关的。此外，治疗筛选显示，靶向STAT3和Wnt信号通路的药物可有效降低HCT116和HT29细胞的细胞活力。因此，我们发现使用同杉碱抑制STAT3和敲低STAT3可显著降低ht29衍生肿瘤球的形成和存活。我们还观察到STAT3磷酸化受表皮生长因子（EGF）调控，诱导PDGFA和Wnt信号级联反应。我们确定了选择性egfr阳性crc中参与肿瘤球形成和存活的潜在基因。结果表明，EGF-STAT3信号通路促进和维持结直肠癌的干细胞性。此外，STAT3和Wnt之间的串扰激活了Wnt/β-catenin信号通路，该信号通路也负责癌症的发生。因此，STAT3被认为是结直肠癌治疗的治疗靶点。本文的在线版本（10.1186/s12929-018-0456-y）包含补充内容，仅供授权用户使用。
Cancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes. In this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs. RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades. We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment. The online version of this article (10.1186/s12929-018-0456-y) contains supplementary material, which is available to authorized users.
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影响因子：
2.7
作者：
Hao, J;Li, TG;Zhao, GQ
通讯作者：
Zhao, GQ
影响因子：
4.2
作者：
Choi, Ji Eun;Bae, Jun Sang;Moon, Woo Sung
通讯作者：
Moon, Woo Sung
影响因子：
--
作者：
Hsu HC;Thiam TK;Lu YJ;Yeh CY;Tsai WS;You JF;Hung HY;Tsai CN;Hsu A;Chen HC;Chen SJ;Yang TS
通讯作者：
Yang TS
影响因子：
3.7
作者：
Cheng CC;Chang J;Huang SC;Lin HC;Ho AS;Lim KH;Chang CC;Huang L;Chang YC;Chang YF;Wu CW
通讯作者：
Wu CW
STAT3 作为 ALDH 和 CD44 /CD24 干细胞样胰腺癌细胞的潜在治疗靶点。
影响因子：
5.2
作者：
Lin L;Jou D;Wang Y;Ma H;Liu T;Fuchs J;Li PK;Lü J;Li C;Lin J
通讯作者：
Lin J