Reck-Notch1 Signaling Mediates miR-221/222 Regulation of Lung Cancer Stem Cells in NSCLC

Abstract

Cancer stem cells (CSCs) contribute to the cancer initiation, metastasis and drug resistance in non-small cell lung cancer (NSCLC). Herein, we identified a miR-221/222 cluster as a novel regulator of CSCs in NSCLC. Targeted overexpression or knockdown of miR-221/222 in NSCLC cells revealed the essential roles of miR-221/222 in regulation of lung cancer cell proliferation, mammosphere formation, subpopulation of CD133+ CSCs and the expression of stemness genes including OCT4, NANOG and h-TERT. The in vivo animal study showed that overexpression of miR-221/222 significantly enhanced the capacity of lung cancer cells to develop tumor and grow faster, indicating the importance of miR-221/222 in tumorigenesis and tumor growth. Mechanistically, Reck was found to be a key direct target gene of miR-221/222 in NSCLC. Overexpression of miR-221/222 significantly suppressed Reck expression, activated Notch1 signaling and increased the level of NICD. As an activated form of Notch1, NICD leads to enhanced stemness in NSCLC cells. In addition, knockdown of Reck by siRNA not only mimicked miR-221/222 effects, but also demonstrated involvement of Reck in the miR-221/222-induced activation of Notch1 signaling, verifying the essential roles of the miR-221/222-Reck-Notch1 axis in regulating stemness of NSCLC cells. These findings uncover a novel mechanism by which lung CSCs are significantly manipulated by miR-221/222, and provide a potential therapeutic target for the treatment of NSCLC.

PD‐L1/p‐STAT3 promotes the progression of NSCLC cells by regulating TAM polarization

“…Cancer stemness is closely related to the occurrence and metastasis of NSCLC 17 . To investigate the effect of αPD‐L1 on stemness of NSCLC cells by regulating TAM/M2 polarization, the protein expression of stemness‐related markers, including CD44, Oct4, Sox2, Bmi‐1 and Nanog were detected by the western blot assay (Figure 5A–C,E–G; Figure S1K‐M).…”

“…Cancer stemness is closely related to the occurrence and metastasis of NSCLC. 17 To investigate the effect of αPD‐L1 on stemness of NSCLC cells by regulating TAM/M2 polarization, the protein expression of stemness‐related markers, including CD44, Oct4, Sox2, Bmi‐1 and Nanog were detected by the western blot assay (Figure 5A–C,E–G ; Figure S1K‐M ). The results showed that the protein expression of stemness‐related markers was up‐regulated after TAM/M2 polarization induced by IL‐13 or NSCLC cells, while αPD‐L1 inhibited this phenomenon.…”

Six MicroRNA Prognostic Models for Overall Survival of Lung Adenocarcinoma

“…Many miRNAs have important roles in the occurrence, progress, and metastasis of lung cancer through regulating a variety of processes, including cancer initiation and progression. Some miRNAs associated with prognostic value have been discovered thus far, such as miR-221 [ 19 ], miR-372 [ 20 ], miR-429 [ 21 ], miR-486 [ 22 ], and miR-137 [ 23 ]. However, many miRNAs are yet to be discovered in LUAD, and their roles are yet to be clarified.…”

Epigenetics and mitochondrial dysfunction insights into the impact of the progression of non‐alcoholic fatty liver disease

“…Furthermore, new discoveries suggest that it may have a role as a cancer biomarker 89 . A cluster of miR‐221/222 has been identified as a marker for breast cancer 90–93 as well as other cancers such as colorectal, glioma, glioblastoma, and lung 49,94–96 . Researchers have also discovered its significance in relation to FLD.…”

“…89 A cluster of miR-221/222 has been identified as a marker for breast cancer [90][91][92][93] as well as other cancers such as colorectal, glioma, glioblastoma, and lung. 49,[94][95][96] Researchers have also discovered its significance in relation to FLD. In 26 individuals with NASH, Ogawa et al 97 detected a significantly elevated level of miR-221/222.…”