TYRO3 promotes chemoresistance via increased LC3 expression in pancreatic cancer.
TYRO3 promotes chemoresistance via increased LC3 expression in pancreatic cancer.
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DOI：
10.1016/j.tranon.2022.101608
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发表时间：
2023-02
影响因子：
5
通讯作者：
Matsura, Tatsuya
中科院分区：
文献类型：
--
作者：
Hara, Kazushi;Horikoshi, Yosuke;Morimoto, Masaki;Nakaso, Kazuhiro;Sunaguchi, Teppei;Kurashiki, Tatsuyuki;Nakayama, Yuji;Hanaki, Takehiko;Yamamoto, Manabu;Sakamoto, Teruhisa;Fujiwara, Yoshiyuki;Matsura, Tatsuya
胰腺癌(PC)是一种侵袭性很强的恶性肿瘤，治疗方法很少，迫切需要改进治疗策略。Tyro3是已知的癌基因，属于受体酪氨酸激酶家族成员，但Tyro3表达与PC耐药的关系尚不清楚。我们对Tyro3进行了功能增强和功能丧失的实验，以确定它是否参与了PC细胞的化疗耐药。用吉西他滨和5-氟尿嘧啶(5-FU)处理PC细胞后，Tyro3基因敲除降低了细胞存活率，促进了细胞凋亡。相反，在过度表达Tyro3的PC细胞中没有观察到这样的影响。已知自噬与癌症化疗耐药有关。然后我们研究了Tyro3对PC细胞自噬的影响。Tyro3过表达可增加PC细胞中Lc3基因的表达水平，并诱导Lc3斑点。氯喹抑制自噬可减轻细胞对吉西他滨和5-FU的耐药性。在异种移植小鼠模型中，Tyro3沉默显著增加了细胞对吉西他滨和5-FU的敏感性。为了进一步研究自噬在胰腺癌患者中的作用，我们用免疫组织化学方法分析了胰腺切除患者组织中Lc3的表达，并将其与疾病预后和Tyro3的表达进行了比较。Lc3表达与预后呈负相关，与Tyro3表达呈正相关。此外，在复发后接受化疗的PC患者中，LC3和Tyro3阳性患者的预后明显较差。这些结果表明，Tyro3-自噬信号通路使PC对吉西他滨和5-FU产生耐药，可能成为解决PC化疗耐药的新靶点。
Pancreatic cancer (PC) is an aggressive malignancy with few treatment options, and improved treatment strategies are urgently required. TYRO3, a member of the TAM receptor tyrosine kinase family, is a known oncogene; however, the relationship between TYRO3 expression and PC chemoresistance remains to be elucidated. We performed gain- and loss-of-function experiments on TYRO3 to examine whether it is involved in chemoresistance in PC cells. TYRO3 knockdown decreased cell viability and enhanced apoptosis following treatment of PC cells with gemcitabine and 5-fluorouracil (5-FU). In contrast, no such effects were observed in TYRO3-overexpressing PC cells. It is known that autophagy is associated with cancer chemoresistance. We then examined effects of TYRO3 on autophagy in PC cells. TYRO3 overexpression increased LC3 mRNA levels and induced LC3 puncta in PC cells. Inhibition of autophagy by chloroquine mitigated cell resistance to gemcitabine and 5-FU. In a xenograft mouse model, TYRO3 silencing significantly increased sensitivity of the cells to gemcitabine and 5-FU. To further investigate the involvement of autophagy in patients with PC, we immunohistochemically analyzed LC3 expression in the tissues of patients who underwent pancreatectomy and compared it with disease prognosis and TYRO3 expression. LC3 expression was negatively and positively correlated with prognosis and TYRO3 expression, respectively. Furthermore, LC3- and TYRO3-positive patients had a significantly worse prognosis among patients with PC who received chemotherapy after recurrence. These results indicated that the TYRO3-autophagy signaling pathway confers PC resistance to gemcitabine and 5-FU, and could be a novel therapeutic target to resolve PC chemoresistance.
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DOI：
10.3390/ph14070677
发表时间：
2021-07-15
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Di Federico A;Tateo V;Parisi C;Formica F;Carloni R;Frega G;Rizzo A;Ricci D;Di Marco M;Palloni A;Brandi G
通讯作者：
Brandi G
影响因子：
5.2
作者：
通讯作者：
--
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy
影响因子：
5.3
作者：
OBRYAN, JP;FRYE, RA;LIU, ET
通讯作者：
LIU, ET
影响因子：
5.2
作者：
Chen, Dehu;Liu, Qinghong;Zhang, Wei
通讯作者：
Zhang, Wei