Effects of Maackia amurensis seed lectin (MASL) on oral squamous cell carcinoma (OSCC) gene expression and transcriptional signaling pathways.
Effects of Maackia amurensis seed lectin (MASL) on oral squamous cell carcinoma (OSCC) gene expression and transcriptional signaling pathways.
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山槐种子凝集素（MASL）对口腔鳞状细胞癌（OSCC）基因表达和转录信号通路的影响。
DOI：
10.1007/s00432-020-03456-8
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发表时间：
2021-03
影响因子：
3.6
通讯作者：
Goldberg GS
中科院分区：
文献类型：
--
作者：
Hamilton KL;Sheehan SA;Retzbach EP;Timmerman CA;Gianneschi GB;Tempera PJ;Balachandran P;Goldberg GS
口腔癌每年导致超过12万人死亡，并影响幸存者的生活质量。超过90%的口腔癌来源于口腔鳞状细胞癌细胞(OSCCs)，这些细胞通常对标准的细胞毒化疗药物具有耐药性。口腔鳞癌细胞通常表现出比未转化的口腔上皮细胞更强的转化生长因子β和PDPn受体活性。山玛瑙种子凝集素(MASL)可以靶向PDPN受体，已被确定为一种可用于治疗口腔癌的新型药物。然而，MASL抑制口腔鳞癌进展的机制尚未明确。在这里，我们进行了细胞迁移和细胞毒性试验，以评估MASL在生理相关浓度下对口腔鳞癌移动性和存活率的影响。然后，我们进行了全面的转录组分析，结合转录因子报告实验，研究了MASL在这些浓度下如何影响OSCC基因的表达。然后用蛋白质印迹法确认关键数据，从蛋白水平评价MASL对基因表达和激酶信号活性的影响。在这项研究中，用于建立口腔鳞状细胞癌模型的HSC-2细胞发现大约15,000个基因表达，MASL显著影响了其中约27%的基因的表达。这些受MASL影响的基因包括转化生长因子β-SMAD、JAK-STAT和WNT-βCTN信号通路的成员。特别是，MASL在RNA和蛋白质水平上降低了PDPN、SOX2和Smad5的表达。MASL还抑制SMAD和MAPK活性，并显示出与阿霉素和5-氟尿嘧啶联合治疗的潜力。综上所述，本研究的结果表明，MASL降低了JAK-STAT、转化生长因子β-SMAD和WNT-βCTN信号通路的活性，从而抑制口腔鳞癌的生长和运动。这些数据表明，应该进行进一步的研究，以确定MASL如何也可以单独或与其他药物联合用于治疗口腔癌。
Oral cancer causes over 120,000 deaths annually and affects the quality of life for survivors. Over 90% of oral cancers are derived from oral squamous cell carcinoma cells (OSCCs) which are generally resistant to standard cytotoxic chemotherapy agents. OSCC cells often exhibit increased TGFβ and PDPN receptor activity compared to nontransformed oral epithelial cells. Maackia amurensis seed lectin (MASL) can target the PDPN receptor and has been identified as a novel agent that can be used to treat oral cancer. However, mechanisms by which MASL inhibits OSCC progression are not yet clearly defined. Here, we performed cell migration and cytotoxicity assays to assess the effects of MASL on OSCC motility and viability at physiologically relevant concentrations. We then performed comprehensive transcriptome analysis combined with transcription factor reporter assays to investigate the how MASL affects OSCC gene expression at these concentration. Key data were then confirmed by western blotting to evaluate the effects of MASL on gene expression and kinase signaling activity at the protein level. MASL significantly affected the expression of about 27% of approximately 15 thousand genes found to be expressed by HSC-2 cells used to model OSCC cells in this study. These genes affected by MASL include members of the TGFβ-SMAD, JAK-STAT, and Wnt-βCTN signaling pathways. In particular, MASL decreased expression of PDPN, SOX2, and SMAD5 at the RNA and protein levels. MASL also inhibited SMAD and MAPK activity and exhibited potential for combination therapy with doxorubicin and 5-fluorouracil. Taken together, results from this study indicate that MASL decreases activity of JAK-STAT, TGFβ-SMAD, and Wnt-βCTN signaling pathways to inhibit OSCC growth and motility. These data suggest that further studies should be undertaken to determine how MASL may also be used alone and in combination with other agents to treat oral cancer.
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