ArticleOncogene2015
TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 86 citations in OpenAlex.
- Effects of extracellular acidity on resistance to chemotherapy treatment: a systematic review.Medical oncology (Northwood, London, England) · 2018Pooled it
- A worm-like nucleic acid nanostructure for gene delivery and endosomal escape via ClC3 ion exchanger.Science advances · 2026Article
- TM9SF4 acts as a receptor mediatingFrontiers in cellular and infection microbiology · 2026Article
- Mapping the genetic landscape of suicide risk: Insights from genomic SEM.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- TM9SF4 is a potential prognostic biomarker in hepatocellular carcinoma.Discover oncology · 2025Article
- Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy.Cell death & disease · 2025Article
- V-ATPase in cancer: mechanistic insights and therapeutic potentials.Cell communication and signaling : CCS · 2024Review
- Determining expression changes of ANO7 and SLC38A4 membrane transporters in colorectal cancer.Heliyon · 2024Article
- Mechanisms of drug resistance in nutrient-depleted colorectal cancer cells: insights into lysosomal and mitochondrial drug sequestration.Biology open · 2024Review
- High ATP6V1B1 expression is associated with poor prognosis and platinum‑based chemotherapy resistance in epithelial ovarian cancer.Oncology reports · 2023Article
- A CRISPR screen in intestinal epithelial cells identifies novel factors for polarity and apical transport.eLife · 2023Article
- Cell-in-cell: a potential biomarker of prognosis and a novel mechanism of drug resistance in cancer.Frontiers in oncology · 2023Review
- The V-ATPases in cancer and cell death.Cancer gene therapy · 2022Review
- Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach.Pharmaceutics · 2022Article
- TM9SF4 is an F-actin disassembly factor that promotes tumor progression and metastasis.Nature communications · 2022Article
- CircCEMIP promotes anoikis-resistance by enhancing protective autophagy in prostate cancer cells.Journal of experimental & clinical cancer research : CR · 2022Article
- Cell-in-Cell Events in Oral Squamous Cell Carcinoma.Frontiers in oncology · 2022Review
- SCG2: A Prognostic Marker That Pinpoints Chemotherapy and Immunotherapy in Colorectal Cancer.Frontiers in immunology · 2022Article
- TM9SF4 is a novel regulator in lineage commitment of bone marrow mesenchymal stem cells to either osteoblasts or adipocytes.Stem cell research & therapy · 2021Article
- Review
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
An inverted pH gradient across the cell membranes is a typical feature of malignant cancer cells that are characterized by extracellular acidosis and cytosol alkalization. These dysregulations are able to create a unique milieu that favors tumor progression, metastasis and chemo/immune-resistance traits of solid tumors. A key event mediating tumor cell pH alterations is an aberrant activation of ion channels and proton pumps such as (H+)-vacuolar-ATPase (V-ATPase). TM9SF4 is a poorly characterized transmembrane protein that we have recently shown to be related to cannibal behavior of metastatic melanoma cells. Here, we demonstrate that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation. We have observed in HCT116 and SW480 colon cancer cell lines that TM9SF4 interacts with the ATP6V1H subunit of the V-ATPase V1 sector. Suppression of TM9SF4 with small interfering RNAs strongly reduces assembly of V-ATPase V0/V1 sectors, thus reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity. Such effects are associated with a significant inhibition of the invasive behavior of colon cancer cells and with an increased sensitivity to the cytotoxic effects of 5-fluorouracil. Our study shows for the first time the important role of TM9SF4 in the aberrant constitutive activation of the V-ATPase, and the development of a malignant phenotype, supporting the potential use of TM9SF4 as a target for future anticancer therapies.
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