Li Xian, Kang Lihua, Han Wenyan, Su Xiulan
Key Laboratory of Medical Cell Biology in Inner Mongolia, Clinical Medical Research Center, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia,010050, China.
Inner Mongolia Medical University, Hohhot, Inner Mongolia,010050, China.
Curr Protein Pept Sci. 2025 Jan 8. doi: 10.2174/0113892037350632241205040150.
Gastric cancer has become one of the major diseases threatening human health. This study aimed to investigate the mechanism of an anticancer bioactive peptide (ACBP) combined with oxaliplatin (OXA) on MKN-45, SGC7901, and NCI-N87 differentiated human gastric cancer cells and GES-1 immortalized human gastric mucosal epithelial cells. The therapeutic effect and action mechanism of short-term intermittent ACBP combined with OXA on nude mice with human gastric cancer were also investigated.
The half-maximal inhibitory concentrations of these agents in these cells were measured by an MTT assay, and cell morphological changes were observed by H&E staining. The expression of Lin28, miR-107, miR-609, and Let-7 in these four cell lines was determined by q-PCR after drug treatment. Lin28 protein expression in these four cell lines treated with these drugs was measured by western blotting. Furthermore, activity and quality of life were observed daily in all tumor-bearing nude mice, and the expression of Lin28 in tumor tissue was determined by immunohistochemistry and RT-PCR.
The results showed that ACBP inhibited the proliferation of MKN-45, SGC7901, and NCI-N87 gastric cancer cells in a dose-dependent manner and weakly suppressed the proliferation of GES-1 cells. Moreover, its inhibitory effect on proliferation was stronger in poorly differentiated gastric cancer cells. ACBP, OXA, and the combination upregulated Lin28 gene expression in MKN-45 cells and downregulated it in SGC7901 and GES-1 cells. ACBP and the combination therapy downregulated Let-7 expression in MKN-45 cells and upregulated Let-7 expression in SGC7901 cells. The combination of ACBP with OXA demonstrated significant anticancer sensitization. Moreover, it also significantly improved the quality of life of tumor-bearing nude mice and reduced the toxic side effects of chemotherapeutic drugs on nude mice.
ACBP alone and in combination with oxaliplatin influenced the expression of tumor stem cell marker gene Lin28 and regulated the expression of microRNAs specifically regulated by Lin28. In addition, the anticancer effects and attenuated sensitization effects of ACBP may be related to the Lin28/miRNA-107 signaling pathway, acting by inhibiting the proliferation of cancerous stem cells. The findings of this study provide a scientific basis for exploring the antitumor mechanism of ACBP alone and combined with chemotherapeutic drugs.
胃癌已成为威胁人类健康的主要疾病之一。本研究旨在探讨一种抗癌生物活性肽（ACBP）与奥沙利铂（OXA）联合作用于MKN - 45、SGC7901和NCI - N87分化型人胃癌细胞以及GES - 1永生化人胃黏膜上皮细胞的机制。还研究了短期间歇性ACBP联合OXA对人胃癌裸鼠的治疗效果及作用机制。
通过MTT法测定这些药物在这些细胞中的半数抑制浓度，并通过苏木精 - 伊红染色观察细胞形态变化。药物处理后，通过q - PCR测定这四种细胞系中Lin28、miR - 107、miR -
609和Let - 7的表达。通过蛋白质印迹法测定用这些药物处理的这四种细胞系中Lin28蛋白的表达。此外，每天观察所有荷瘤裸鼠的活动及生活质量，并通过免疫组织化学和RT - PCR测定肿瘤组织中Lin28的表达。
结果表明，ACBP以剂量依赖性方式抑制MKN - 45、SGC7901和NCI - N87胃癌细胞的增殖，并对GES - 1细胞的增殖有较弱的抑制作用。此外，其对低分化胃癌细胞增殖的抑制作用更强。ACBP、OXA及其联合用药上调MKN - 45细胞中Lin28基因的表达，下调SGC7901和GES - 1细胞中Lin28基因的表达。ACBP及联合治疗下调MKN - 45细胞中Let - 7的表达，上调SGC7901细胞中Let - 7的表达。ACBP与OXA联合显示出显著的抗癌增敏作用。此外，它还显著改善了荷瘤裸鼠的生活质量，降低了化疗药物对裸鼠的毒副作用。
ACBP单独及与奥沙利铂联合影响肿瘤干细胞标志物基因Lin28的表达，并调节受Lin28特异性调控的微小RNA的表达。此外，ACBP的抗癌作用和增敏作用可能与Lin28/miRNA - 107信号通路有关，通过抑制癌干细胞的增殖发挥作用。本研究结果为探索ACBP单独及与化疗药物联合的抗肿瘤机制提供了科学依据。
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