Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT activation

Abstract

Cancer stem cells (CSC) play a pivotal role in cancer metastasis and resistance to therapy. Previously, we compared the phosphoproteomes of breast cancer stem cells (BCSCs) enriched subpopulation and non-BCSCs sorted from breast cancer patient-derived xenograft (PDX), and identified a function unknown protein, transmembrane and coiled-coil domain family 3 (TMCC3) to be a potential enrichment marker for BCSCs. We demonstrated greater expression of TMCC3 in BCSCs than non-BCSCs and higher expression of TMCC3 in metastatic lymph nodes and lungs than in primary tumor of breast cancer PDXs. TMCC3 silencing suppressed mammosphere formation, ALDH activity and cell migration in vitro, along with reduced tumorigenicity and metastasis in vivo. Mechanistically, we found that AKT activation was reduced by TMCC3 silencing, but enhanced by TMCC3 overexpression. We further demonstrated that TMCC3 interacted directly with AKT through its 1-153 a.a. domain by cell-free biochemical assay in vitro and co-immunoprecipitation and interaction domain mapping assays in vivo. Based on domain truncation studies, we showed that the AKT-interacting domain of TMCC3 was essential for TMCC3-induced AKT activation, self-renewal, and metastasis. Clinically, TMCC3 mRNA expression in 202 breast cancer specimens as determined by qRT-PCR assay showed that higher TMCC3 expression correlated with poorer clinical outcome of breast cancer, including early-stage breast cancer. Multivariable analysis identified TMCC3 expression as an independent risk factor for survival. These findings suggest that TMCC3 is crucial for maintenance of BCSCs features through AKT regulation, and TMCC3 expression has independent prognostic significance in breast cancer. Thus, TMCC3 may serve as a new target for therapy directed against CSCs.

B7-H3 confers stemness characteristics to gastric cancer cells by promoting glutathione metabolism through AKT/pAKT/Nrf2 pathway

“…[ 67 ] Moreover, silencing transmembrane and coiled-coil domain family 3 (TMCC3) reduced AKT activation and inhibited the self-renewal and metastasis of breast cancer stem cells. [ 68 ] Herein, our data showed that B7-H3 overexpression elevated p-AKT and Nrf2 protein expression. Furthermore, perifosine treatment reversed the effect of B7-H3 on GSH metabolism and the stemness of GC cells.…”

Unveiling IL6R and MYC as Targeting Biomarkers in Imatinib-Resistant Chronic Myeloid Leukemia through Advanced Non-Invasive Apoptosis Detection Sensor Version 2 Detection

“…The solute carrier (SLC) and ATP-binding cassette (ABC) transporter superfamilies are critical in the processes of drug absorption, distribution, metabolism, and elimination, marking their importance in the field of pharmacology [34]. Through next-generation sequencing (NGS) RNAseq analysis, we observed significant upregulation of stemness-associated genes (TMCC3, UGT2B7, PCAT18, SOX13, REG1A) among the top differentially expressed genes (DEGs) in K562-IR cells compared to their non-resistant counterparts [35][36][37]. Notably, SLC25A48 and SLC30A8 emerged as the most upregulated SLC transporters, with fold changes (log 2 ) of 7.57 and 6.3, respectively, making them among the top 50 upregulated DEGs.…”

The interplay between IGF-1R signaling and Hippo-YAP in breast cancer stem cells

“…Previously, we had established three PDXs of human breast cancer, including BC0145, BC0244, and BC0350R1 in mice and identified H2K d− CD24 − CD44 + in BC0145 and ALDH + cells in BC0244 and BC0350R1 as markers for their CSCs [8,10]. Subsequently, our comparative phosphoproteomic analysis revealed greater phosphorylated YAP at Serine 61 (2.7 and 19.1 folds) and Threonine 63 (2.8 and 18.7 folds) in BCSCs than in non-BCSCs in two repeated experiments [11] (Additional file 1: Fig.…”