miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1

Abstract

Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/ AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.

Role of Transmembrane 4 L Six Family 1 in the Development and Progression of Cancer

“…High TM4SF1 expression was associated with older patient age, smoking habits, and poor survival Ye et al, 2019 Lung cancer Kaplan-Meier analysis TM4SF1 expression was correlated with survival time, tumor size, lymph node metastasis, distant metastasis, overall survival, and clinical stage Fu et al, 2020 Lung cancer qRT-PCR Increased TM4SF1 expression was significantly associated with early post-operative relapse and shorter survival Kao et al, 2003 Lung cancer Kaplan-Meier survival analysis High TM4SF1 expression was correlated with shorter median overall survival and PFS Ma et al, 2018 Pancreatic cancer published profiles of the TCGA dataset TM4SF1 expression was associated with tobacco smoking, diabetes, tumor size, clinical stage, T stage, lymph node metastasis, distant tumor metastasis, tumor cell venous invasion, lymphatic invasion, and poor overall survival Xu D. et al, 2020 Pancreatic cancer IHC High TM4SF1 expression group showed better survival and lower locoregional recurrence rate than the low expression group Zheng B. et al, 2015 higher TM4SF1 expression levels have relatively good prognosis (Gordon et al, 2003(Gordon et al, , 2009(Gordon et al, , 2011. The function of TM4SF1 in different kinds of cancer was shown in Table 2.…”

“… Bae et al (2011) reported that TM4SF1 was abundantly expressed on mesenchymal stem cells (MSCs) and functions as a surface protein marker that distinguishes MSCs from diverse cell sources, particularly fibroblastic connective tissues. MiR-30a/c significantly decreased the cancer stem-like characteristics of non-small cell lung cancer-initiating cells by inhibiting TM4SF1 in vitro and in vivo ( Ma et al, 2018 ). Silencing of TM4SF1 completely suppressed the transcription of the pluripotency factors sex-determining region Y box 2 (Sox2) and octamer-binding transcription factor-4 (Oct4), suggesting that TM4SF1 could promote the CSC traits of breast cancer ( Gao et al, 2016 ).…”

“…As shown in Table 2 , shorter median survival time, shorter median overall survival, shorter progression-free survival, early post-operative relapse, older age, and smoking were associated with high TM4SF1 expression, which has prognostic value, is a risk factor for poor outcomes, and could be useful as a tumor biomarker for patients with lung cancer ( Kao et al, 2003 ; Ma et al, 2018 ; Ye et al, 2019 ). In human glioma, the expression level of TM4SF1 was markedly higher in higher-grades (III–IV) glioma tissues than in lower grade (I–II) tumor tissues ( Wang et al, 2015 ).…”

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

“…Due to the downregulation of miR-30, the overexpression of TM4SF1 in CSCs promotes tumorsphere formation and the proliferation of CSCs. In other words, miR-30 interferes with CSC development and induces cell apoptosis [40].…”

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

“… 18 Competing endogenous RNAs (ceRNAs), natural decoys that compete for a common pool of microRNAs (miRNA, miR), represent a novel layer of gene regulation by systematically functionalizing miRNA response element (MRE)-harboring non-coding RNAs, such as long non-coding RNAs (lncRNAs), pseudogenes, and circular RNAs (circRNAs), and forming complex miRNA-mediated ceRNA networks. 19 , 20 , 21 , 22 , 23 The perturbation of ceRNA crosstalk will disrupt the balance of cellular processes and functions, leading to development of diseases such as cancer. 24 , 25 , 26 Recently, a study reported that lncRNAs H19 and HULC, stimulated by oxidative stress, regulate cell migration and invasion in CHOL by increasing the expression of IL-6 and CXCR4 in the inflammatory process using ceRNA methods of sponging let-7a/let-7b and miR-372/miR-373, respectively.…”