Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis worldwide. However, the pathogenesis of HCC remains poorly understood. In this study, we found that NOL12 was significantly overexpressed in independent HCC datasets from TCGA database. We confirmed that the expression level of NOL12 was upregulated in human HCC tissues and cell lines by RT‐qPCR. High expression of NOL12 is associated with worse reduced overall survival (OS), high pathological grade, node metastasis, and advanced clinical stage in patients with HCC. Moreover, knockdown of NOL12 dramatically inhibits the proliferation and metastasis of HCC cells in vitro and in vivo. CIBERSORTx analysis revealed that twelve types of tumor‐infiltrating immune cells (TICs) are correlated with NOL12 expression. The risk signature based on 8 NOL12‐related genes is an independent prognostic factor for patients with HCC. The OS rate of patients in the low‐risk score group was better than that in the high‐risk score group. In addition, the total tumor mutation burden (TMB) in the high‐risk score group increased significantly, and the risk scores could be used as an alternative indicator of immune checkpoint inhibitor (ICI) response. In conclusion, our findings indicated that NOL12 might be involved in the progression of HCC and can be used as a potential therapeutic target. Moreover, the NOL12‐related risk signature may have predictive relevance with regard to ICI therapy.

XBP1 variant 1 (Xv1) is the most abundant XBP1 variant and is highly enriched across cancer types but nearly none in normal tissues. Its expression is associated with poor patients’ survival and is specifically required for survival of malignant cells, but the underlying mechanism is not known. Here we report that Xv1 upregulates the polyglutamylase tubulin tyrosine ligase-like 6 (TTLL6) and promotes mitosis of cancer cells. Like the canonical XBP1, Xv1 mRNA undergoes unconventional splicing by IRE1α under endoplasmic reticulum stress, but it is also constitutively spliced by IRE1β. The spliced Xv1 mRNA encodes the active form of Xv1 protein (Xv1s). RNA sequencing in HeLa cells revealed that Xv1s overexpression regulates expression of genes that are not involved in the canonical unfolded protein response, including TTLL6 as a highly upregulated gene. Gel shift assay and chromatin immunoprecipitation revealed that Xv1s bind to the TTLL6 promoter region. Knockdown of TTLL6 caused death of cancer cells but not benign and normal cells, similar to the effects of knocking down Xv1. Moreover, overexpression of TTLL6 partially rescued BT474 cells from apoptosis induced by either TTLL6 or Xv1 knockdown, supporting TTLL6 as an essential downstream effector of Xv1 in regulating cancer cell survival. TTLL6 is localized in the mitotic spindle of cancer cells. Xv1 or TTLL6 knockdown resulted in decreased spindle polyglutamylation and interpolar spindle, as well as congression failure, mitotic arrest and cell death. These findings suggest that Xv1 is essential for cancer cell mitosis, which is mediated, at least in part, by increasing TTLL6 expression.

Cancer is a major category of diseases that need to be addressed urgently, bringing a huge burden to the world. Gastric cancer (GC) is a frequent malignant tumor of the digestive system with the highest incidence and mortality rate among all tumors. The purpose of this study was to explore the mechanism of action of TMEM45A in pan-cancer and gastric cancer. First, GEO and TCGA database were employed to analyze the expression of TMEM45A in GC patients. Then, we determined the association between TMEM45A expression and survival of GC patients using the Kaplan-Meier Plotter database and TCGA database and verified the accuracy of TMEM45A in predicting prognosis. Next, we analyzed the effect of CTHRC expression on TIICs in GC tissues. A prognostic model was constructed using immunomodulatory genes associated with TMEM45A. The specificity and accuracy of the model were verified. TMEM45A expression was markedly higher in GC tissue than in normal tissue. GC patients with TMEM45A overexpression had a poor prognosis. The AUC value of 5-year survival on the ROC curve was 0.705, indicating that TMEM45A is a reliable prognostic factor and can be used as a clinicopathological indicator alone to predict patient prognosis. Three high-risk immunomodulatory genes (CXCR4 and TGFB1) and one low-risk immunomodulatory gene (PDCD1) were obtained using both univariate and multivariate COX methods. These three immunomodulatory molecules were used to construct prognostic models. GC patients with TMEM45A overexpression have a poor prognosis and are associated with immune cell infiltration. Hence, TMEM45A is a fairly reliable independent prognostic marker.

Background: RNF43, a single transmembrane circular E3 ubiquitin ligase, has been identified as a tumor suppressor for a variety of cancers, including ovarian cancer, gastric cancer, pancreatic cancer, endometrial cancer and colorectal cancer. It is even considered to be carcinogenic driver mutations in cholangiocarcinoma, ovarian cancer, gastric cancer, endometrial cancer and colorectal cancer (CRC). However, the correlation between RNF43 mutation and CRC immunotherapy has not been reported yet. Methods: We evaluated the role of RNF43 in CRC using publicly available data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). An in-house Chinese CRC cohort (n=2290) was used for the analysis of immune-related markers. The relationship between clinical pathologic features and RNF43 were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: In the MSKCC cohort, a total of 108 CRC patients receiving immunotherapy were enrolled, of which 38 (34.9%) were over 60-year-old and 61 (56.0%) were male. RNF43 mutation was significantly associated with high TMB and high MSI score (all p <0.05). Besides these, RNF43 mutation was discovered to be enriched in MSI instable. Kaplan-Meier survival analysis showed that patients with RNF43 mutation obtained better OS compared to RNF43 wild-type (not reach vs. 13 months, HR, 0.12; 95% CI 0.03-0.49; p=0.0034). In the TCGA cohort, CRC patients of stage I-IV were 16.6%, 38.5%, 28.2% and 14.2%, respectively. All of these patients received radiation therapy. No association was observed between RNF43 and OS (HR, 1.83; 95% CI 0.66-5.07; p=0.2479). In the in-house Chinese CRC cohorts, 210 (9.2%) patients carried RNF 43 mutations, of which 123 patients (58.6%) were male. RNF43 mutations were significantly associated with higher TMB levels (p 1% (p=0.0110) in the in-house Chinese RCC cohorts. Citation Format: Changjun Yu, Weibiao Kang, Yu Yuan, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5089.

Gastric cancer is a common solid tumor of the digestive system, This research aimed to investigate the relationships among CTHRC1 expression, prognostic values and tumor-infiltrating immune cells (TIICs) in GC patients.The expression of CTHRC1 in gastric cancer patients was analyzed using the GEPIA database and the TCGA database. The relationship between CTHRC1 expression and survival of gastric cancer patients was then explored using the Kaplan-Meier Plotter database and TCGA database.Subsequently, we explored whether there was an associative effect between the expression of CTHRC1 and TIICs in gastric cancer tissues. Then we constructed a prognostic model using immunomodulatory genes related to CTHRC1 and verified the specificity and accuracy of the model.Compared with normal tissues, the expression of CTHRC1 was significantly upregulated in gastric cancer tissues. And the high expression of CTHRC1 was associated with poor prognosis of gastric cancer patients.It is suggested that CTHRC1 is a reliable prognostic indicator for predicting the prognosis of gastric cancer patients.Then we successively used univariate and multivariate COX methods to obtain three high-risk immunomodulatory genes (TGFB2, CXCR4 and NT5E) and one low-risk immunomodulatory gene (TNFRSF18) associated with CTHRC1. These four immunomodulatory genes were used to construct a prognostic model for gastric cancer.Gastric cancer patients with high CTHRC1 expression have a poor prognosis and are associated with immune cell infiltration. Therefore, CTHRC1 can be considered as a potentially reliable prognostic indicator for gastric cancer patients.

Amine oxidase copper containing 3 (AOC3) had been reported to play an important regulatory role in the biological functional pathways, immune microenvironment and cellular function. However, the potential function of AOC3 in cancer had not been fully studied. We conducted a comprehensive analysis of the potential function of AOC3 in pan-cancer using multiple online databases and analytical methods, including mutations and differential expression analysis, pathway analysis and immune analysis. Then, the function of the AOC3 was assessed in colorectal cancer (CRC) cells. Pan-cancer analysis results show that the highest mutation frequency of ACO3 in embryonic tumor patients, in most cancers, the expression of AOC3 is significantly downregulated and the differential expression of AOC3 was mainly concentrated in CRC and female tumors. Enrichment analysis showed that AOC3 was involved in PPAR signaling pathway. In addition, bioinformatic investigation revealed a link between the AOC3 with immune cell infiltration in the tumor microenvironment. Cell experiments have confirmed that AOC3 can significantly regulate the apoptosis and cycle progression of CRC cells. In summary, our study not only comprehensively analyzed the potential mechanisms of AOC3 in pan-cancer, but also validated the potential regulatory role of AOC3 through CRC cell experiments.