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Cancer-therapy-induced mucosal injury (CMI) is a common and deleterious complication that affects patients undergoing cancer therapies. This study was aimed at elucidating knowledge bases and predicting research trends of this field, by analyzing the bibliographic data of CMI.The bibliographic data of CMI from 2001 to 2021 were extracted from the Web of Science Core Collection database in March 2022. After screening, a total of 8181 articles and reviews were included in the study. CiteSpace and VOSviewer were applied to analyze and visualize cooperation, cooccurrence, cocitation, and coupling networks.A steady increase in publications and a burst of citation since 2019 were seen in the subject. Supportive Care in Cancer, International Journal of Radiation Oncology Biology Physics, Annals of Oncology, Cancer, and Radiotherapy and Oncology were the most influential journals of this field. The University of Adelaide, University of Texas MD Anderson Cancer Center, and Memorial Sloan Kettering Cancer Center were the top three most productive institutions. ST Sonis, RV Lalla, JB Epstein, and DMK Keefe were the authors with impressive publications and citations. The intellectual base was the publication network of improved treatments based on updating knowledge of CMI. The future trends would be the pathogenesis of CMI, mechanism-based interventions, microbiota of oral and gastrointestinal mucosa, and photobiomodulation.This study introduced the evolving publication network and predicted the research trends of CMI, which helped researchers to obtain detailed and reliable knowledge of the discipline, and focus on the most urgent unsolved problems in this field.

Purpose: The limited efficacy of chimeric antigen receptor (CAR) T-cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3.CAR T cells with several solid cancer types. Experimental Design: We evaluated B7-H3 expression in many human solid cancer and normal tissue samples. The efficacy of the combinatorial therapy with B7-H3.CAR T cells and the deacetylase inhibitor SAHA with several solid cancer types and the potential underlying mechanisms were characterized with in vitro and ex vivo experiments. Results: B7-H3 is expressed in most of the human solid tumor samples tested, but exhibits a restricted expression in normal tissues. B7-H3.CAR T cells selectively killed B7-H3 expressing human cancer cell lines in vitro. A low dose of SAHA upregulated B7-H3 expression in several types of solid cancer cells at the transcriptional level and B7-H3.CAR expression on human transgenic T-cell membrane. In contrast, the expression of immunosuppressive molecules, such as CTLA-4 and TET2, by T cells was downregulated upon SAHA treatment. A low dose of SAHA significantly enhanced the antitumor activity of B7-H3.CAR T cells with solid cancers in vitro and ex vivo, including orthotopic patient-derived xenograft and metastatic models treated with autologous CAR T-cell infusions. Conclusions: Our results show that our novel strategy which combines SAHA and B7-H3.CAR T cells enhances their therapeutic efficacy with solid cancers and justify its translation to a clinical setting.

Objective Whether tumor mutation burden (TMB) affects prognosis and immune infiltration of tumor patients is controversial. We designed and conducted a multi-omics study with the aim of investigating the prognostic value of TMB and the relationship between TMB and immune infiltration in head and neck squamous cell carcinoma (HNSCC). Methods: TMB scores were calculated from the mutation data of 506 HNSCC samples from The Cancer Genome Atlas (TCGA), and the patients were divided into low- and high-TMB groups according to the TMB score quartiles. Differentially expressed genes (DEGs) between the low-TMB and high-TMB groups were identified. Immune cell infiltration and survival analyses were conducted between groups. Results: High TMB in HNSCC patients was associated with a poor prognosis, large primary tumor size, advanced clinical stage and a human papillomavirus (HPV)-negative status. A total of 576 DEGs were identified, and gene set enrichment analysis (GSEA) revealed that the DEGs in the low-TMB group were enriched in immune-related pathways. Four hub genes were significantly associated with prognosis, and mutations in these genes affected immune infiltration. The estimated fractions of B memory cells and CD4+ memory resting cells were higher in the low-TMB group than in the high-TMB group, and B cell and CD4+T cell infiltration was positively correlated with prognosis in HNSCC patients. Conclusions: HNSCC patients with low TMB have better prognoses than those with high TMB, and TMB might affect B cell and CD4+T cell infiltration.

MicroRNAs (miRNAs) have been recently found in the mitochondria, and were named “mitomiRs”, but their function has remained elusive. Here, we aimed to assess the presence and function(s) of mitomiRs in tongue squamous cell carcinoma (TSCC). Methods: miRNA microarray was performed in paired TSCC cell lines, Cal27 and its chemoresistant counterpart, Cal27-re. Decreased expression of mitomiRs in chemoresistant cells was characterized. The functions of mitomiRs were investigated by a series of in vitro and in vivo experiments. Results: Differential microarray analysis identified downregulation of mitomiR-5787 in Cal27-re cells. We knocked down mitomiR-5787 in parental cells and upregulated its expression in cisplatin-resistant cells. The sensitivity of TSCC cells to cisplatin was regulated by miR-5787. The glucose metabolism assay suggested that reduced expression of miR-5787 changed the balance of glucose metabolism by shifting it from oxidative phosphorylation to aerobic glycolysis. Xenograft experiments in BALB/c-nu mice further verified the in vitro results. Reduced expression of miR-5787 contributes to chemoresistance in TSCC cells by inhibiting the translation of mitochondrial cytochrome c oxidase subunit 3 (MT-CO3). The prognostic analysis of 126 TSCC patients showed that the patients with low expression of miR-5787 and/or MT-CO3 had poor cisplatin sensitivity and prognosis. Conclusions: Mitochondrial miR-5787 could regulate cisplatin resistance of TSCC cells and affect oxidative phosphorylation and aerobic glycolysis. Downregulation of miR-5787 inhibited the translation of MT-CO3 to regulate cisplatin resistance of TSCC. Mitochondrial miR-5787 and MT-CO3 can be used as predictive biomarkers or therapeutic targets for cisplatin chemotherapy resistance.

Summary Cisplatin-based neoadjuvant chemotherapy has been shown to improve survival in patients with squamous cell carcinoma (SCC), but clinical biomarkers to predict chemosensitivity remain elusive. Here, we show the long noncoding RNA (lncRNA) LINC01011, which we termed cisplatin-sensitivity-associated lncRNA (CISAL), controls mitochondrial fission and cisplatin sensitivity by inhibiting BRCA1 transcription in tongue SCC (TSCC) models. Mechanistically, we found CISAL directly binds the BRCA1 promoter and forms an RNA-DNA triplex structure, sequestering BRCA1 transcription factor-GABPA away from the downstream regulatory binding region. Importantly, the clinical relevance of these findings is suggested by the significant association of CISAL and BRCA1 expression levels in TSCC tumors with neoadjuvant chemosensitivity and overall survival. We propose a new model where lncRNAs are tethered at gene promoter by RNA-DNA triplex formation, spatially sequestering transcription factors away from DNA-binding sites. Our study uncovers the potential of CISAL-BRCA1 signaling as a potential target to predict or improve chemosensitivity., Graphical Abstract, Highlights • CISAL enhances mitochondrial fission and cisplatin sensitivity in TSCC cells through BRCA1 • CISAL directly binds the BRCA1 promoter and forms an RNA-DNA triplex structure • CISAL sequesters GABPA away from regulatory binding at BRCA1 promoter • High CISAL predicts favorable neoadjuvant chemosensitivity and prognosis of TSCC patients, Biological Sciences; Molecular Biology; Cell Biology; Cancer

Objectives Despite substantial advances in treatment, clinical outcomes for oral squamous cell carcinoma (OSCC) remain unsatisfactory. Tumor-infiltrating lymphocytes (TILs) are an important prognostic factor for patients and are heterogeneous. Some studies have suggested that TCF1/TCF7+ T cells and tertiary lymphatic structure/organ (TLS) play an important role in tumor immunity. However, how they affect tumor immunity and whether they are related to prognosis in OSCC have not been reported in detail. Materials and methods We isolated OSCC cells and performed single-cell RNA sequencing (scRNA-seq). We used immunohistochemistry (IHC) to analyze the relationship between TLSs and prognosis. Multiplex immunohistochemistry (MIHC), flow cytometry (FCM) and spatial analysis were performed to verify the characteristics of TCF1/TCF7+ T cells. The prognostic significance and upstream regulatory network of the TCF1/TCF7+ T cell subpopulation were determined by multivariate analysis and Scenic software. Results We found a strong association between TCF1/TCF7+ T cell subsets, TLSs and prognosis. The results suggested that TCF1/TCF7+ T cells express high levels of TLS-related genes and low levels of immune checkpoint molecules. Finally, we found that TCF1/TCF7+ T cells were significantly associated with favorable outcomes. We also describe the upstream drivers that these cells rely on. Conclusions TCF1/TCF7+ T cells could be used as a new therapeutic target to regulate the immune response of OSCC and are expected to be a new prognostic marker.

Purpose: The overall biological roles and clinical significance of most long noncoding RNAs (lncRNA) in chemosensitivity are not fully understood. We investigated the biological function, mechanism, and clinical significance of lncRNA NR_034085, which we termed miRNA processing–related lncRNA (MPRL), in tongue squamous cell carcinoma (TSCC). Experimental Design: LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues. The functional roles of MPRL were demonstrated by a series of in vitro and in vivo experiments. The miRNA profiles, RNA pull-down, RNA immunoprecipitation, serial deletion analysis, and luciferase analyses were used to investigate the potential mechanisms of MPRL. Results: We found that MPRL expression was significantly upregulated in TSCC cell lines treated with cisplatin and transactivated by E2F1. MPRL controlled mitochondrial fission and cisplatin sensitivity through miR–483-5p. In exploring the underlying interaction between MPRL and miR–483-5p, we identified that cytoplasmic MPRL directly binds to pre–miR–483 within the loop region and blocks pre–miR–483 recognition and cleavage by TRBP–DICER-complex, thereby inhibiting miR–483-5p generation and upregulating miR–483-5p downstream target-FIS1 expression. Furthermore, overexpression or knockdown MPRL altered tumor apoptosis and growth in mouse xenografts. Importantly, we found that high expression of MPRL and pre–miR–483, and low expression of miR–483-5p were significantly associated with neoadjuvant chemosensitivity and better TSCC patients’ prognosis. Conclusions: We propose a model in which lncRNAs impair microprocessor recognition and are efficient of pre-miRNA cropping. In addition, our study reveals a novel regulatory network for mitochondrial fission and chemosensitivity and new biomarkers for prediction of neoadjuvant chemosensitivity in TSCC. These findings uncover a novel mechanism by which lncRNA determines mitochondrial fission and cisplatin chemosensitivity by inhibition of pre-miRNA processing and provide for the first time the rationale for lncRNA and miRNA biogenesis for predicting chemosensitivity and patient clinical prognosis.

miRNAs that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNAs (mitomiR). mitomiRs have been shown to modulate the translational activity of the mitochondrial genome, yet their role in mitochondrial DNA (mtDNA) transcription remains to be determined. Here we report that the mitomiR-2392 regulates chemoresistance in tongue squamous cell carcinoma (TSCC) cells by reprogramming metabolism via downregulation of oxidative phosphorylation and upregulation of glycolysis. These effects were mediated through partial inhibition of mtDNA transcription by mitomiR-2392 rather than through translational regulation. This repression required specific miRNA–mtDNA base pairing and Argonaute 2. mitomiR-2392 recognized target sequences in the H-strand and partially inhibited polycistronic mtDNA transcription in a cell-specific manner. A retrospective analysis of TSCC patient tumors revealed a significant association of miR-2392 and regulated mitochondrial gene expression with chemosensitivity and overall survival. The clinical relevance of targeted mitochondrial genes was consistently validated by The Cancer Genome Atlas RNA sequencing in multiple types of cancer. Our study revealed for the first time the role of mitomiR in mtDNA transcription and its contribution to the molecular basis of tumor cell metabolism and chemoresistance. Significance: These findings uncover a novel mechanism by which mitomiRNA regulates mitochondrial transcription and provide rationale for use of mitomiRNA and mtDNA-encoded genes to predict chemosensitivity and patient clinical prognosis.