Lactic acid is a “metabolic waste” product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells’ effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.

Purpose. Bladder cancer is one of the most common urological malignancies worldwide, and approximately 90% of bladder cancer cases are histologically typed as bladder urothelial carcinoma (BLCA). Exosomes are 30 to 200 nm extracellular vesicles that transport microRNAs, long noncoding RNAs (lncRNAs), mRNAs, circular RNAs, and proteins across tissues and through circulation. Urinary exosomes may contain genetic information from tumor cells. Herein, we explored the clinical significance of urinary exosomal lncRNA telomerase RNA component (TERC) levels to provide an urgently needed diagnostic and prognostic biomarker for BLCA. Materials and Methods. In this study, we used RNA-sequencing of samples from four BLCA patients and three healthy controls to identify that TERC was differentially expressed in urinary exosomes. We then used quantitative PCR in different types of clinical samples to validate the biomarker and analyzed results using receiver operating characteristic curves. Results. We found that TERC was significantly upregulated in urinary exosomes from BLCA patients compared with those from healthy controls ( ). Urinary exosomal TERC showed higher sensitivity (78.65%) and accuracy (77.78%) than existing indicators including nuclear matrix protein-22 and urine cytometry. Using the cut-off value 4.302, the area under the curve for urinary exosomal TERC was 0.836 (95% confidence interval: 0.768–0.891, ). Furthermore, this noninvasive assay could distinguish low-grade and high-grade tumors ( ). Conclusions. TERC is enriched in urinary exosomes from BLCA patients. Urinary exosomal TERC could become a diagnostic and prognostic biomarker for BLCA that allows clinicians to realize noninvasive detection of BLCA.

Bladder cancer (BLCA) is one of the cancers that is highly sensitive to specific non-invasive tumor biomarkers that facilitate early diagnosis. Exosome-derived long non-coding RNAs (lncRNAs) hold promise as diagnostic biomarkers for BLCA. In this study, we employed RNA-sequencing to compare the expression patterns of lncRNAs in urine exosomes from three BLCA patients and three healthy individuals. RMRP displayed the most significant differential expression. Elevated RMRP expression levels were observed in urinary and plasma exosomes from BLCA patients compared with those from healthy individuals. RMRP exhibited significant associations with certain BLCA patient clinicopathological features, including tumor stage, poor prognosis, and tumor grade. Combined diagnosis using RMRP in urine and plasma exosomes demonstrated a superior diagnostic performance with receiver operating characteristic curve analysis. RMRP was found to be related to BLCA tumor progression and the cell migration and invasion processes via the miR-206/G6PD axis both in vitro and in vivo. Mechanistically, RMRP serves as an miR-206 sponge, as suggested by dual-luciferase reporter assays and RNA immunoprecipitation. Our study suggests that the combined diagnosis of RMRP in urinary and plasma exosomes can serve as an excellent non-invasive diagnostic biomarker for BLCA patients. Additionally, targeting the RMRP/miR-206/G6PD axis holds promise as a therapeutic strategy for BLCA.

Muscle-invasive bladder cancer is susceptible to metastasis and has a poor prognosis. A better understanding of the biological process and molecular mechanisms associated with bladder cancer aggressiveness could lead to the development of effective strategies to prevent metastasis. In this study, we identified that the long noncoding RNA telomerase RNA component (TERC) was significantly upregulated in invasive bladder urothelial carcinoma tissues. Loss of TERC inhibited the proliferation, migration, and invasion of bladder cancer cells in vitro and suppressed tumor growth in vivo. N6-methyladenosine modification mediated the upregulated TERC expression levels in bladder cancer cells. TERC facilitated nuclear export of polypyrimidine tract–binding protein 3 (PTBP3) through the nuclear pore complex, which enabled PTBP3 to bind to the 3′ untranslated region of retinoid X receptor α (RXRA) mRNA. PTBP3 binding enhanced RXRA mRNA stability and upregulated its protein levels, leading to elevated expression of downstream fatty acid uptake–related molecules. Through this mechanism, TERC remodeled fatty acid metabolism and thereby promoted bladder cancer growth and invasion. Furthermore, TERC levels in exosomes were elevated in the urine and plasma of patients with urothelial carcinoma. High levels of urine exosomal TERC were associated with lymph node metastasis and larger tumor diameter, whereas high plasma exosomal TERC was linked to lymph node metastasis and high pathologic grade. Overall, these findings indicate that TERC represents a potential target for therapeutic development and a putative liquid biopsy biomarker for the diagnosis of urothelial carcinoma. Significance: TERC is a potential therapeutic target and biomarker in bladder cancer that undergoes m6A-mediated upregulation and remodels fatty acid metabolism by enhancing RXRA levels through nuclear export PTBP3 to promote tumor aggressiveness.

Supplementary file 5 shows the top 10 differentially upregulated lncRNAs filtered from the RNA-seq results using the criteria of |log2FC| > 2.5 and P < 0.05 and ranked by abundance.

Supplementary file 4 provides the reporter gene sequences of WT-RXRA 3'UTR and MT-RXRA 3'UTR used in the dual-luciferase reporter gene assay.