CD98 heavy chain as a prognostic biomarker and target for cancer treatment

Abstract

The SLC3A2 gene encodes for a cell-surface transmembrane protein CD98hc (4F2). CD98hc serves as a chaperone for LAT1 (SLC7A5), LAT2 (SLC7A8), y+LAT1 (SLC7A7), y+LAT2 (SLC7A6), xCT (SLC7A11) and Asc1 (SLC7A10) providing their recruitment to the plasma membrane. Together with the light subunits, it constitutes heterodimeric transmembrane amino acid transporters. CD98hc interacts with other surface molecules, such as extracellular matrix metalloproteinase inducer CD147 (EMMPRIN) and adhesion receptors integrins, and regulates glucose uptake. In this way, CD98hc connects the signaling pathways sustaining cell proliferation and migration, biosynthesis and antioxidant defense, energy production, and stem cell properties. This multifaceted role makes CD98hc one of the critical regulators of tumor growth, therapy resistance, and metastases. Indeed, the high expression levels of CD98hc were confirmed in various tumor tissues, including head and neck squamous cell carcinoma, glioblastoma, colon adenocarcinoma, pancreatic ductal adenocarcinoma, and others. A high expression of CD98hc has been linked to clinical prognosis and response to chemo- and radiotherapy in several types of cancer. In this mini-review, we discuss the physiological functions of CD98hc, its role in regulating tumor stemness, metastases, and therapy resistance, and the clinical significance of CD98hc as a tumor marker and therapeutic target.

Microbiome Dysbiosis Is Associated with Castration Resistance and Cancer Stemness in Metastatic Prostate Cancer

“…CSCs are thought to have a high capacity for migration and colonization and are widely believed to be the basis of metastasis across cancer types [ 19 , 20 , 21 ]. To assess the microbiome’s relation to these factors, a list of transcriptional CSC markers was first collected from the literature [ 42 , 43 , 44 , 45 ]. Among others, this list includes CD44, SOX2, and NANOG ( Supplementary Materials Table S1 ).…”

“…Among other markers, MYC, EGFR, and SLC3A2 were consistently downregulated, with a greater abundance of most species. Hence, a lesser abundance of these species, as observed in these patients with CRPC, may correlate with increased MYC, EGFR, and SLC3A2 expression, increased MYC, EGFR, and SLC3A2 signaling, and, ultimately, a CSC-like phenotype [ 43 , 44 ]. Interestingly, overexpression of EGFR has been implicated in the metastasis of prostate cancers to the bone [ 43 ].…”

“…Interestingly, overexpression of EGFR has been implicated in the metastasis of prostate cancers to the bone [ 43 ]. SLC3A2 has similarly been shown to regulate proliferation, migration, and therapy resistance in cancer cells [ 44 ]. We propose that ablation of the microbiome, as induced by androgen deprivation therapy, may promote the growth and development of CSCs.…”

“…A list of genes known to be implicated in CR at a transcriptional level was collected from the literature [ 18 ]. A list of known CSC markers was similarly collected [ 42 , 43 , 44 , 45 ]. Two of these studies investigate CSC markers, with a particular emphasis on prostate cancer.…”

Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes

“…Accordingly, the amino acid transporter SLC7A11, which provides the limiting amino acid cysteine for glutathione synthesis, is an important controller of ferroptosis in cancer cells [51,52]. The recruitment of SLC7A11 to the plasma membrane requires a protein chaperone, called SLC3A2, and the functionally active complex is a heterodimer consisting of the chaperone SLC3A2 and the actual transporter SLC7A11 [53,54]. Therefore, we examined the expression of the transporter as well as the chaperone in the four cancer cell lines.…”