LINC00887 was more highly expressed in clear cell renal cell carcinoma (ccRCC) models and was linked to changes that could help tumors evade immune attack, according to experiments in cancer cells, immune-cell cultures and mice. Higher LINC00887 tracked with faster glycolysis, the process cells use to break down sugar for energy, and with a shift in macrophages toward an M2 state, measured through markers and cell proportions.
The same models pointed to UPF1 as a counterweight. LINC00887 and UPF1 moved in opposite directions: reducing LINC00887 increased UPF1, while lowering UPF1 restored the more glycolytic pattern linked to LINC00887. The authors also reported that LINC00887 physically interacted with UPF1, although the detailed mechanism connecting the two remains unresolved.
A metabolism signal with immune consequences
When researchers increased LINC00887 in ccRCC cells, the cells showed higher levels of glycolysis-related proteins, greater extracellular acidification, more glucose uptake, more lactate release and more ATP. Reducing the RNA produced the opposite pattern. The analysis also found that LINC00887 was more highly expressed in cancer-related samples than in normal tissue and was positively associated with glycolytic gene signatures.
Culture fluid from cells with extra LINC00887 was associated with more M2 markers and more CD68+CD206+ macrophages, alongside fewer M1 markers and fewer CD68+CD86+ cells. The reported pattern was reduced by OXM. In related experiments, lowering UPF1 in cancer cells was associated with stronger M2 polarization, while the glycolysis inhibitor 2-DG shifted the macrophage pattern toward M1 markers.
The immune effects extended to CD8+ T cells in a macrophage co-culture system. With UPF1 reduced and no 2-DG, CD8+ T-cell proliferation was lower and apoptosis was higher. Adding 2-DG reversed those findings, and CD8+ T-cell cytotoxicity was higher when glycolysis was inhibited. These were laboratory measures of immune-cell function, not patient treatment outcomes.
UPF1 was tied to tumor behavior
The study’s human-data analysis also pointed in the same direction, although it showed associations rather than proof of cause. UPF1 messenger RNA was lower in ccRCC tumors and in more malignant settings, while higher UPF1 expression was associated with more favorable survival. In cell experiments, reducing UPF1 was associated with greater viability, proliferation, migration and invasion, and with less apoptosis. Increasing UPF1 produced the reciprocal findings.
The analysis drew on 501 ccRCC and 69 normal samples from the TCGA-KIRC dataset. It also examined a single-cell dataset containing two tumor and two adjacent tissues. That dataset included 40,474 cells before quality control and 39,518 after filtering, which were grouped into 16 clusters and seven annotated cell subtypes. The small number of tissue specimens limits how confidently those single-cell patterns can be generalized.
The mouse test
The researchers then tested the proposed pathway in 24 female BALB/c mice. The animals received Renca kidney cancer cells carrying either a control sequence or a sequence that reduced LINC00887. The groups were then reassigned to control or UPF1-silencing treatments and followed for five weeks, with tumor volume recorded every seven days.
Mice with LINC00887 reduced had slower tumor growth, lower tumor lactate and less M2 macrophage infiltration, along with a higher proportion of CD8+ T cells. Silencing UPF1 reversed those reported changes. The result was consistent with an LINC00887-UPF1 link connecting cancer-cell metabolism to the immune environment, but the study did not establish whether the same pathway changes treatment outcomes in people.
What remains to be tested
The findings do not settle how LINC00887 regulates UPF1 or which direct RNA targets of UPF1 drive the glycolytic changes. Evidence for the macrophage effect came from conditioned-media and marker-based cellular assays. The reported metabolic rescue experiments also showed directional changes without supplied numeric effect sizes or confidence intervals.
The core experiments used glycolytic assays, gene and protein measurements, flow cytometry for macrophage and CD8+ T-cell measures, and an LDH-release test for CD8+ T-cell cytotoxicity. Cell experiments were performed in triplicate, with two-group comparisons using Student’s t-test and multiple-group comparisons using one-way analysis of variance with Tukey testing. The study defined statistical significance as a p-value below 0.05, but the supplied findings do not include numeric effect sizes or confidence intervals.
Paper data and sources
Original title: UPF1-dependent glycolysis driven by LINC00887 facilitates macrophage M2 polarization in clear cell renal cell carcinoma
Authors: Wu J, Wang J, Weng J et al.
Journal/Repository: Frontiers in immunology
Status: Peer-reviewed
First online: 2026-10-08
DOI: Not available
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