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We have investigated the combined influence of CSCs, circRNA (hsa_circ_0003222), and immune checkpoint inhibitors in NSCLC progression and therapy resistance. We constructed lung CSCs (LCSCs; PC9 and A549). The effects of hsa_circ_0003222 in vitro were determined by cell counting, colony and sphere formation, and Transwell assays. A tumor xenograft model of metastasis and orthotopic model were built for in vivo analysis. We found that hsa_circ_0003222 was highly expressed in NSCLC tissues and LCSCs. Higher levels of hsa_circ_0003222 were associated with the stage, metastasis, and survival rate of patients with NSCLC. Reduced levels of hsa_circ_0003222 decreased tumor cell proliferation, migration, invasion, stemness-like properties, and chemoresistance. The silencing of hsa_circ_0003222 was found to downregulate PHF21B expression and its downstream, \u03b2-catenin by relieving the sponging effect of miR-527. Moreover, silencing hsa_circ_0003222 alleviated NSCLC resistance to anti-programmed cell death-ligand 1 (PD-L1)-based therapy in vivo. Our data demonstrate the significant role of hsa_circ_0003222 in NSCLC cell stemness-like properties. The manipulation of circRNAs in combination with anti-PD-L1 therapy may alleviate NSCLC stemness and progression.<\/jats:p>","DOI":"10.1038\/s41419-021-04095-8","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T14:02:39Z","timestamp":1629900159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["hsa_circ_0003222 accelerates stemness and progression of non-small cell lung cancer by sponging miR-527"],"prefix":"10.1038","volume":"12","author":[{"given":"Changhui","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4606-1250","authenticated-orcid":false,"given":"Jiaqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqing","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runbo","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinchen","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7343-9706","authenticated-orcid":false,"given":"Jun","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6878-7936","authenticated-orcid":false,"given":"Wei","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3950-3030","authenticated-orcid":false,"given":"Baohui","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6332-5089","authenticated-orcid":false,"given":"Xueyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"4095_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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