Lysine methyltransferase 5C increases the proliferation and metastatic abilities of clear cell renal cell carcinoma via aerobic glycolysis.

Among all types of renal cancer, clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype and is associated with a high risk of metastasis and recurrence. Histone modifications regulate several biological processes that are fundamental to the development of cancer. Lysine methyltransferase 5C (KMT5C; also known as SUV420H2) is an epigenetic modifier responsible for the trimethylation of H4K20, which drives critical cellular events, including genome integrity, cell growth and epithelial­mesenchymal transition (EMT), in various types of cancer. However, the role of KMT5C in ccRCC remains unclear. As such, the expression and function of KMT5C in ccRCC were investigated in the present study. KMT5C expression was significantly increased in ccRCC tissues compared with normal tissues (P<0.0001), and it was closely associated with the overall survival rate of patients with ccRCC. By establishing ccRCC cell lines with KMT5C expression knockdown, the role of KMT5C in the maintenance of aerobic glycolysis in ccRCC cells via the regulation of several vital glycolytic genes was identified. Additionally, KMT5C promoted the proliferation and EMT of ccRCC cells by controlling crucial EMT transcriptional factors. Together, these data suggested that KMT5C may act as an oncoprotein, guide molecular diagnosis, and shed light on novel drug development and therapeutic strategies for patients with ccRCC.

DPP9 Stabilizes NRF2 to Suppress Ferroptosis and Induce Sorafenib Resistance in Clear Cell Renal Cell Carcinoma.

The KEAP1-NRF2 axis is the principal regulator of cellular responses to oxidative and electrophilic stressors. NRF2 hyperactivation is frequently observed in many types of cancer and promotes cancer initiation, progression, metastasis, and resistance to various therapies. Here, we determined that dipeptidyl peptidase 9 (DPP9) is a regulator of the KEAP1-NRF2 pathway in clear cell renal cell carcinoma (ccRCC). DPP9 was markedly overexpressed at the mRNA and protein levels in ccRCC, and high DPP9 expression levels correlated with advanced tumor stage and poor prognosis in patients with ccRCC. Protein affinity purification to identify functional partners of DPP9 revealed that it bound to KEAP1 via a conserved ESGE motif. DPP9 disrupted KEAP1-NRF2 binding by competing with NRF2 for binding to KEAP1 in an enzyme-independent manner. Upregulation of DPP9 led to stabilization of NRF2, driving NRF2-dependent transcription and thereby decreasing cellular reactive oxygen species levels. Moreover, DPP9 overexpression suppressed ferroptosis and induced resistance to sorafenib in ccRCC cells, which was largely dependent on the NRF2 transcriptional target SLC7A11. Collectively, these findings indicate that the accumulation of DPP9 results in hyperactivation of the NRF2 pathway to promote tumorigenesis and intrinsic drug resistance in ccRCC. SIGNIFICANCE: DPP9 overcomes oxidative stress and suppresses ferroptosis in ccRCC by binding to KEAP1 and promoting NRF2 stability, which drives tumor development and sorafenib resistance.

Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor.

The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic-area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.

Integrative proteogenomic characterization of early esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) is malignant while the carcinogenesis is still unclear. Here, we perform a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 ESCC patients, covering 9 histopathological stages and 3 phases. Proteogenomics elucidates cancer-driving waves in ESCC progression, and reveals the molecular characterization of alcohol drinking habit associated signatures. We discover chromosome 3q gain functions in the transmit from nontumor to intraepithelial neoplasia phases, and find TP53 mutation enhances DNA replication in intraepithelial neoplasia phase. The mutations of AKAP9 and MCAF1 upregulate glycolysis and Wnt signaling, respectively, in advanced-stage ESCC phase. Six major tracks related to different clinical features during ESCC progression are identified, which is validated by an independent cohort with another 256 samples. Hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) is considered as a drug target in ESCC progression. This study provides insight into the understanding of ESCC molecular mechanism and the development of therapeutic targets.

Proteogenomic characterization of MiT family translocation renal cell carcinoma.

Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication.

Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals new therapeutic strategies.

Chemotherapy and targeted therapy are the major treatments for gastric cancer (GC), but drug resistance limits its effectiveness. Here, we profile the proteome of 206 tumor tissues from patients with GC undergoing either chemotherapy or anti-HER2-based therapy. Proteome-based classification reveals four subtypes (G-I-G-IV) related to different clinical and molecular features. MSI-sig high GC patients benefit from docetaxel combination treatment, accompanied by anticancer immune response. Further study reveals patients with high T cell receptor signaling respond to anti-HER2-based therapy; while activation of extracellular matrix/PI3K-AKT pathway impair anti-tumor effect of trastuzumab. We observe CTSE functions as a cell intrinsic enhancer of chemosensitivity of docetaxel, whereas TKTL1 functions as an attenuator. Finally, we develop prognostic models with high accuracy to predict therapeutic response, further validated in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemotherapy and targeted therapy in GC.

Increased DNA Polymerase Epsilon Catalytic Subunit Expression Predicts Tumor Progression and Modulates Tumor Microenvironment of Hepatocellular Carcinoma.

Backgrounds: Liver hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and POLE, playing an important role in maintaining genetic stability, is closely connected with cancer prognosis. This study aimed to explore the significance role of POLE in HCC prognosis, clinical treatment and tumor immune microenvironment based on large-scale multiply cohorts. Methods: First, we found that the expression of POLE was prominently higher in tumor tissues than in normal tissues, and was closely related to clinical stage, grade and patient outcomes. Second, we found that patients with high POLE expression had significantly aggressive progression, indicating effective predictive role of POLE expression for Asian, male, low-risk HCC patients. Additionally, POLE mutation frequency was detected in several datasets with available genomic-wide data. Results: 130 HCC samples from real-world Renji cohort were included to demonstrate that elevated POLE expression was significantly connected to the invasive progression and poor prognosis. More importantly, the expression of POLE was closely related to the anti-tumoral activity of immune cells and immune checkpoints expression, suggesting a bright prospect of POLE as a predictive biomarker in immunotherapy. Conclusion: In conclusion, this study revealed that high expression of POLE significantly correlated to the malignant progression, poor prognosis and anti-tumoral activity of immune cells in HCC. Thus, POLE could function as a biomarker for the early diagnosis, prognosis, immune-excluded tumor microenvironment and response to immunotherapy of HCC.

Integrated proteogenomic characterization of urothelial carcinoma of the bladder.

BACKGROUND: Urothelial carcinoma (UC) is the most common pathological type of bladder cancer, a malignant tumor. However, an integrated multi-omics analysis of the Chinese UC patient cohort is lacking. METHODS: We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 116 Chinese UC patients, comprising 45 non-muscle-invasive bladder cancer patients (NMIBCs) and 71 muscle-invasive bladder cancer patients (MIBCs). RESULT: Proteogenomic integration analysis indicated that SND1 and CDK5 amplifications on chromosome 7q were associated with the activation of STAT3, which was relevant to tumor proliferation. Chromosome 5p gain in NMIBC patients was a high-risk factor, through modulating actin cytoskeleton implicating in tumor cells invasion. Phosphoproteomic analysis of tumors and morphologically normal human urothelium produced UC-associated activated kinases, including CDK1 and PRKDC. Proteomic analysis identified three groups, U-I, U-II, and U-III, reflecting distinct clinical prognosis and molecular signatures. Immune subtypes of UC tumors revealed a complex immune landscape and suggested the amplification of TRAF2 related to the increased expression of PD-L1. Additionally, increased GARS, related to subtype U-II, was validated to promote pentose phosphate pathway by inhibiting activities of PGK1 and PKM2. CONCLUSIONS: This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in urothelial carcinoma of the bladder.

Increased expression of tribbles homolog 3 predicts poor prognosis and correlates with tumor immunity in clear cell renal cell carcinoma: a bioinformatics study.

Tribbles homolog 3 (TRIB3), a pseudokinase that regulates multiple intracellular signaling pathways, has been reported to promote the growth of multiple tumors. However, its role in clear cell renal cell carcinoma (ccRCC) remains unelucidated. We evaluated the role of TRIB3 in ccRCC using publicly available data from The Cancer Genome Atlas and analyzed its relationship with the tumor microenvironment; moreover, we used gene knockout and overexpression techniques to detect the effects of TRIB3 on the biological behavior of ccRCC cells. RT-qPCR and western blotting were used to detect transfection efficiency, and the invasiveness of ccRCC cells was determined by Transwell migration assays. We found that TRIB3 overexpression was significantly associated with increased grade, stage, and distant metastasis, positively correlated with ccRCC invasiveness, and also an independent risk factor for overall survival (OS). In addition, 361 differentially expressed genes (DEGs) related to TRIB3 were identified. Functional enrichment analysis showed that DEGs were mainly enriched in humoral immune responses, collagen-containing extracellular matrix, and serine hydrolase activity. Immune landscape characterization revealed that TRIB3 expression was significantly and negatively associated with CD8+ T and hematopoietic stem cells, whereas it was positively associated with NK T and macrophage M1 cells. Single-cell sequencing showed that localization and binding targets of TRIB3 mainly involved monocytes/macrophages and CD4+ and CD8+ T cells. Overall, our study revealed that elevated TRIB3 expression represents a promising prognostic marker for ccRCC patients and may play a key role in tumor microenvironment modulation.

A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population.

Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1-3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

Identification of prognostic biomarkers in papillary renal cell carcinoma and PTTG1 may serve as a biomarker for predicting immunotherapy response.

OBJECTIVE: This study aims to identify potential prognostic and therapeutic biomarkers in papillary renal cell carcinoma (pRCC). METHODS: Two microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. The protein-protein interaction (PPI) networks and functional annotations of DEGs were established. Survival analysis was utilized to evaluate the prognostic significance of the DEGs and the association between the expression level of candidate biomarkers and various tumour-infiltrating immune cells was explored. The role of PTTG1 in tumour microenvironments (TME) was further explored using Single-cell RNA-seq and its prognostic and therapeutic significance was validated in Fudan University Shanghai Cancer Centre (FUSCC) cohort. RESULTS: Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with patients' prognosis. The expression level of PTTG1 was found to be significantly associated with lymphocytes, immunomodulators, and chemokine in the TCGA cohort. Single-cell RNA-seq information indicated that PTTG1 was strongly associated with the proliferation of T cells. In the FUSCC cohort, the expression level of PTTG1 was also statistically significant for both progression-free survival (PFS) and overall survival (OS) prediction (HR = 2.683, p < .001; HR = 2.673, p = .001). And higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in the FUSCC cohort (χ2=3.99, p < .05). CONCLUSIONS: Eight genes were identified as a prognostic biomarker and the expression level of PTTG1 was also found to serve as a potential predictor for ICB response in pRCC patients.Key messages:Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with pRCC patients' prognosis.Expression level of PTTG1 was significantly associated with tumour microenvironment including lymphocytes, immunomodulators, and chemokines.Higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in FUSCC cohort.

Construction of an Immune Escape-Related Signature in Clear Cell Renal Cell Carcinoma and Identification of the Relationship between IFNAR1 and Immune Infiltration by Multiple Immunohistochemistry.

BACKGROUND: In the past decade, immunotherapy has been widely used in the treatment of various tumors, such as PD-1/PD-L1 inhibitors. Although clear cell renal cell carcinoma (ccRCC) has been shown to be sensitive to immunotherapy, it is effective only in several cases, which brings great obstacles to anti-tumor therapy for patients. Lawson et al. have successfully identified 182 "core cancer innate immune escape genes" whose deletion makes cancer cells more sensitive or resistant to T-cell attack. METHODS: In this research, we sought to explore genes closely associated with ccRCC among the 182 core cancer innate immune escape genes. We used online databases to screen mutated genes in ccRCC, and then used ConsensusClusterPlus to cluster clinical samples to analyze differences in clinical prognosis and immune components between the two subgroups. In addition, the immune escape score was calculated using lasso cox regression, and a stable tumor immune escape-related nomogram was established to predict the overall survival of patients. RESULTS: Higher immune escape score was significantly correlated with shorter survival time. Meanwhile, through the validation of the external cohort and the correlation analysis of the immune microenvironment, we proved that IFNAR1 is the key gene regulating immune escape in ccRCC, and we also found that the function of IFNAR1 in promoting immune activation is achieved by facilitating the infiltration of CD4+ T cells and CD8+ T cells. IFNAR1 regulates the malignant behavior of ccRCC by inhibiting the proliferation and migration properties. CONCLUSIONS: IFNAR1 may become a key biomarker for evaluating the efficacy of ccRCC immunotherapy and may also be a potential target for immunotherapy.

Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK-GATA3-ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. SIGNIFICANCE: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK-GATA3-ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

The Prognostic Value of Programmed Death-Ligand 1 in a Chinese Cohort With Clear Cell Renal Cell Carcinoma.

Objective: To investigate the association between tumor PD-L1 expression and patient survival to determine whether PD-L1 represents an independent prognostic feature for patients with non-metastatic clear cell renal cell carcinoma (RCC). Patients and Methods: The tissue bank of the Fudan University Shanghai Cancer Center was queried to identity tissue samples of patients treated with radical nephrectomy, for non-metastatic sporadic clear cell RCC (ccRCC) between 2008 and 2015. Real-time polymerase chain reaction and immunohistochemistry staining was performed to detect the expression level of PD-L1 in paired cancer tissue and paracancerous tissue. Results: Three-hundred-and-thirty patients were enrolled in this study, with a mean age of 55.0 years at surgery and a mean tumor size of 5.2 cm. Two-hundred-and-forty-two (73.3%) and 88 (26.7%) patients showed a high and low expression of PD-L1 mRNA, respectively, while 254 patients had positive PD-L1 immunohistochemistry staining. Two-hundred-and-ninety-two patients had consistent results for mRNA and the PD-L1 protein based on these different detection methods. Patients with high PD-L1 expression were more likely to exhibit adverse pathologic features including an advanced T stage (P = 0.002) and lymph node metastasis (P = 0.044). The Kaplan-Meier curves of PFS and OS stratified by PD-L1 expression had a statistically significant difference. PD-L1 expression maintained a significant predictive role for PFS and OS in the multivariate cox model. Conclusions: Our data suggests that PD-L1 correlates with prognosis in RCC and targeting the PD-1/PD-L1 pathway should be considered in the treatment of RCC patients.

APC/CCDH1 synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression.

Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication. Herein, we find that the anaphase-promoting complex/cyclosome (APC/C) synchronizes ribose-5-phosphate levels and DNA synthesis during the cell cycle. In late G1 and S phases, transketolase-like 1 (TKTL1) is overexpressed and forms stable TKTL1-transketolase heterodimers that accumulate ribose-5-phosphate. This accumulation occurs by asymmetric production of ribose-5-phosphate from the non-oxidative pentose phosphate pathway and prevention of ribose-5-phosphate removal by depleting transketolase homodimers. In the G2 and M phases after DNA synthesis, expression of the APC/C adaptor CDH1 allows APC/CCDH1 to degrade D-box-containing TKTL1, abrogating ribose-5-phosphate accumulation by TKTL1. TKTL1-overexpressing cancer cells exhibit elevated ribose-5-phosphate levels. The low CDH1 or high TKTL1-induced accumulation of ribose-5-phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner. Here we reveal that the cell cycle control machinery regulates DNA synthesis by mediating ribose-5-phosphate sufficiency.

High expression of F2RL3 correlates with aggressive features and poor survival in clear cell renal cell carcinoma.

Background: Specific lifestyle factors including tobacco-exposure are vital etiologic factors for renal cell carcinoma (RCC), F2R Like Thrombin/Trypsin Receptor 3 (F2RL3) is associated with smoking but it is unknown whether its expression translate into poor survival of clear cell RCC (ccRCC). In the current study, the expression profiling and prognostic value of F2RL3 in Chinese patients with ccRCC were investigated. Methods: Using Quantitative PCR analysis and immunohistochemistry, the relative expression levels of F2RL3 in 367 paired ccRCC and adjacent normal tissues were calculated. Cox regression analysis was used to identify independent prognostic factors and Kaplan-Meier analysis and a log-rank test were employed to evaluate the prognostic value of F2RL3. Results: We observed that high expression of F2RL3 mRNA and protein were strongly correlated with shorten progression-free survival (PFS) of ccRCC with hazard ratios (HR; 95% confidence interval (CI)) of 2.060 (1.410-3.009) and 1.657 (1.193-2.300), respectively, as well as with poor overall survival (OS) with HRs (95%CI) of 2.826 (1.713-4.662) and 1.712 (1.140-2.569), respectively. After adjustment for confounding factors including smoking status, elevated HRs (95%CI) of 2.113 (1.445-3.089) and 1.692 (1.218-2.352) were presented for PFS, respectively, and 2.936 (1.777-4.851) and 1.811 (1.203-2.725) were present for OS, respectively. Meanwhile, increased F2RL3 mRNA and protein level were reported to significantly associate with smoking-exposure and well-known prognostic factors (higher TNM stage and ISUP grade). Conclusion: These findings suggested that F2RL3 mRNA and protein level in ccRCC is a robust predictor of poorly prognostic phenotype. Exploring the causal relevance of F2RL3 in ccRCC development further warrants in the future study.

SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression.

BACKGROUND: Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations. SPOP (Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting that SPOP may be a potential driver of prostate cancer. The aim of this work was to investigate how SPOP mutations contribute to prostate cancer development and progression. METHODS: To identify molecular mediators of the tumor suppressive function of SPOP, we performed a yeast two-hybrid screen in a HeLa cDNA library using the full-length SPOP as bait. Immunoprecipitation and Western Blotting were used to analyze the interaction between SPOP and ATF2. Cell migration and invasion were determined by Transwell assays. Immunohistochemistry were used to analyze protein levels in patients' tumor samples. RESULTS: Here we identified ATF2 as a bona fide substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes multiple Ser/Thr (S/T)-rich degrons in ATF2 and triggers ATF2 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting ATF2 degradation in prostate cancer cells and contribute to facilitating prostate cancer cell proliferation, migration and invasion. CONCLUSION: SPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion.

Author Correction: The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common adult renal neoplasm and its incidence continues to increase. Collagen is the most abundant extracellular matrix protein in stroma, and contributes to the development and progression of ccRCC. We examined the human collagen type XXIII α1 chain (COL23A1) expression in ccRCC and the relationship between COL23A1 and patients' survival. We found COL23A1 mRNA was elevated in tumor compared with adjacent normal tissues, which was further validated by TCGA cohort. IHC results from 151 ccRCC cases suggested that high COL23A1 expression correlated with larger tumor size (P = 0.017) and advanced T stage (P = 0.011). The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P = 0.002). In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P = 0.017). Furthermore, COL23A1 knockdown repressed proliferation of ccRCC cell lines by blocking cell cycle progression. Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1. Our data indicate that COL23A1 may be a novel prognostic indicator in ccRCC and might be a specific and accessible biomarker as well as a potential new target for clinical diagnosis of ccRCC.