雌激素诱导的 LncRNA，LINC02568，通过反式和顺式机制促进雌激素受体阳性乳腺癌的发展和耐药性,Advanced Science

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雌激素诱导的 LncRNA，LINC02568，通过反式和顺式机制促进雌激素受体阳性乳腺癌的发展和耐药性
Advanced Science ( IF 14.3 ) Pub Date : 2023-07-05 , DOI: 10.1002/advs.202206663
Xue Chen _{1,

2,

3} , Jian-Cheng Ding _{1,

2,

3} , Guo-Sheng Hu _{1,

2,

3} , Xing-Yi Shu _{1,

2,

3} , Yan Liu ₄ , Jun Du _{1,

2,

3} , Zi-Jing Wen _{1,

2,

3} , Jun-Yi Liu ₅ , Hai-Hua Huang ₆ , Guo-Hui Tang ₄ , Wen Liu _{1,

2,

3}

Affiliation

内分泌治疗是雌激素受体（ER）阳性乳腺癌患者的一线治疗。然而，对内分泌治疗药物的原发性和获得性耐药仍然是临床上的主要挑战。这项工作鉴定了一种雌激素诱导的 lncRNA LINC02568，它在 ER 阳性乳腺癌中高表达，在体外细胞生长、体内肿瘤发生以及内分泌治疗耐药性中发挥重要作用。从机制上讲，这项工作证明 LINC02568 通过在细胞质中海绵 miR-1233-5p 稳定 ESR1 mRNA，从而调节雌激素/ER α诱导的基因转录激活。同时，LINC02568 通过调节细胞核中顺式的碳酸酐酶 CA12，有助于肿瘤特异性 pH 稳态。LINC02568 的双重功能共同促进乳腺癌细胞生长和肿瘤发生以及内分泌治疗耐药性。靶向 LINC02568 的反义寡核苷酸 (ASO) 可显着抑制 ER 阳性乳腺癌细胞的体外生长和体内肿瘤发生。此外，针对LINC02568的ASO与内分泌治疗药物或CA12抑制剂U-104的联合治疗对肿瘤生长表现出协同作用。总而言之，这些发现揭示了 LINC02568在 ER 阳性乳腺癌中调节 ER α信号传导和 pH 稳态的双重机制，并表明靶向 LINC02568 可能代表临床上的潜在治疗途径。

"点击查看英文标题和摘要"

Estrogen-Induced LncRNA, LINC02568, Promotes Estrogen Receptor-Positive Breast Cancer Development and Drug Resistance Through Both In Trans and In Cis Mechanisms

Endocrine therapy is the frontline treatment for estrogen receptor (ER) positive breast cancer patients. However, the primary and acquired resistance to endocrine therapy drugs remain as a major challenge in the clinic. Here, this work identifies an estrogen-induced lncRNA, LINC02568, which is highly expressed in ER-positive breast cancer and functional important in cell growth in vitro and tumorigenesis in vivo as well as endocrine therapy drug resistance. Mechanically, this work demonstrates that LINC02568 regulates estrogen/ERα-induced gene transcriptional activation in trans by stabilizing ESR1 mRNA through sponging miR-1233-5p in the cytoplasm. Meanwhile, LINC02568 contributes to tumor-specific pH homeostasis by regulating carbonic anhydrase CA12 in cis in the nucleus. The dual functions of LINC02568 together contribute to breast cancer cell growth and tumorigenesis as well as endocrine therapy drug resistance. Antisense oligonucleotides (ASO) targeting LINC02568 significantly inhibits ER-positive breast cancer cell growth in vitro and tumorigenesis in vivo. Furthermore, combination treatment with ASO targeting LINC02568 and endocrine therapy drugs or CA12 inhibitor U-104 exhibits synergistic effects on tumor growth. Taken together, the findings reveal the dual mechanisms of LINC02568 in regulating ERα signaling and pH homeostasis in ER-positive breast cancer, and indicated that targeting LINC02568 might represent a potential therapeutic avenue in the clinic.

更新日期：2023-07-05

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