Background: Emerging evidence suggested that aberrant alternative splicing (AS) is pervasive event in development and progression of cancer. However, the information of aberrant splicing events involved in colorectal carcinogenesis and progression is still elusive.Materials and Methods: In this study, splicing data of 499 colon adenocarcinoma cases (COAD) and 176 rectum adenocarcinoma (READ) with clinicopathological information were obtained from The Cancer Genome Atlas (TCGA) to explore the changes of alternative splicing events in relation to the carcinogenesis and prognosis of colorectal cancer (CRC). Gene interaction network construction, functional and pathway enrichment analysis were performed by multiple bioinformatics tools.Results: Overall, most AS patterns were more active in CRC tissues than adjacent normal ones. We detected altogether 35391 AS events of 9084 genes in COAD and 34900 AS events of 9032 genes in READ, some of which were differentially spliced between cancer tissues and normal tissues including genes of SULT1A2, CALD1, DTNA, COL12A1 and TTLL12. Differentially spliced genes were enriched in biological process including muscle organ development, cytoskeleton organization, actin cytoskeleton organization, biological adhesion, and cell adhesion. The integrated predictor model of COAD showed an AUC of 0.805 (sensitivity: 0.734; specificity: 0.756) while READ predictor had an AUC of 0.738 (sensitivity: 0.614; specificity: 0.900). In addition, a number of prognosis-associated AS events were discovered, including genes of PSMD2, NOL8, ALDH4A1, SLC10A7 and PPAT.Conclusion: We draw comprehensive profiles of alternative splicing events in the carcinogenesis and prognosis of CRC. The interaction network and functional connections were constructed to elucidate the underlying mechanisms of alternative splicing in CRC.

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Pepsinogen C (PGC) belongs to the aspartic protease family and is secreted by gastric chief cells. PGC could be activated to pepsin C and digests polypeptides and amino acids, but as a zymogen PGC’s functions is unclear. In normal physiological conditions, PGC is initially detected in the late embryonic stage and is mainly expressed in gastric mucosa. The in situ expression of PGC in gastric mucosa is decreased considerably in the process of superficial gastritis → atrophic gastritis → gastric cancer (GC), proving that PGC is a comparatively ideal negative marker of GC. Serum PGC, and PGA levels and the PGA/PGC ratio have satisfactory sensitivity, specificity and price–quality ratio for predicting high GC risk. Ectopic PGC expression is significantly increased in prostate cancer, breast cancer, ovary cancer and endometrial cancer. In those sex-related cancers high level PGC expression indicates better prognosis and longer survival. The regulation of PGC expression involves genetic and epigenetic alteration of the encoding PGC gene, hormones modulation and interactions between PGC with other transcription factors and protein kinases. More and more research evidence hinted that PGC has strong correlation with cancer. In the systematic review, we respectively elaborate the structure, potential physiological functions, expression characteristics and regulation of PGC, and especially focus on the relationship between PGC expression and cancer to highlight the role of PGC in the tumorigenesis and its application value in clinical practice.

Retinoids exhibit multiple functions through interaction with nuclear retinoid receptors and have growth-suppressive activity on gastric cancer cells. To better understand the roles of nuclear retinoid receptors during gastric carcinogenesis, we have used in situ hybridization to investigate expression of retinoic acid receptors (RARs) and retinoid x receptors (RXRs) in premalignant and malignant formalin-fixed paraffin-embedded gastric tissues. Histological sections of eight normal, 17 distal normal and nine gastric cancer tissues were hybridized with non-radioactive RNA probes for subtypes of RAR and RXR. Expression of RARα, RARβ, RARγ, RXRα and RXRβ was found in most cell types in gastric mucosa tissues from normal individuals as well as in distal normal tissues from cancer patients. Expression of RARα and RARβ were found in three and seven cancer tissues, respectively, and levels of RXRα mRNA were significantly decreased in poorly differentiated cancer tissues. Among the five investigated nuclear retinoid receptors, only expression of RARα mRNA was significantly decreased in intestinal metaplasia, dysplasia and cancer tissues when compared to adjacent normal tissues. In conclusion, normal gastric mucosa expressed both RARs and RXRs, which supports the physiological role of retinoic acid on normal gastric mucosa. The decrease in RARα expression in premalignant and malignant gastric tissues suggests a significant role of RARα during gastric carcinogenesis. © 1999 Cancer Research Campaign

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Gastric tumorigenesis is a multistep process initiated by chronic superficial gastritis (SG), followed by atrophic gastritis (AG), then intestinal metaplasia (IM), and finally by dysplasia and adenocarcinoma according to the Correa model. Pepsinogen C (PGC) decreases gradually during progression of cancer, which makes PGC an ideal negative marker for GC. To explore the correlation between PGC and other positive tumor markers in different gastric diseases, we observed the expression of PGC, MG7‐Ag, MMP9, NM23, Ki‐67, and E‐cadherin by immunohistochemistry, quantitative RT‐PCR, and immunoblot analysis. Our results showed that in SG, PGC was highly expressed while malignant phenotype markers were rarely expressed. In contrast with SG, malignant phenotype markers were highly expressed while the positive rate of PGC reached only 1.44% in GC. So there was no coexpression of PGC and malignant phenotype markers in SG or GC tissues. Only in the AG group, which is well‐known to be gastric precancerous disease, coexpression of PGC and malignant phenotype markers was detected. Our results suggested that the expression of PGC in AG was negatively correlated with that of MG7‐Ag and MMP9. Of all AG, those with low expression of PGC and high expression of MG7‐Ag and MMP9 may possess a greater potential of malignant transformation. Combined detection of negative marker PGC and positive markers MG7‐Ag and MMP9 could be used as a potential follow‐up panel for monitoring dynamical progression of AG and improving the detection efficiency of high‐risk individuals of gastric cancer, and then taking necessary interventions on the target population.

Background It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers. However, the panoramic picture of pepsinogen gene family in human cancer is not clear. This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer. Method Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer‐related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers. Results PGs expression profiles appear different in 33 tumors. The transcriptional expression of PGs was detected in 16 of all 33 tumors. PGC was highly expressed in cholangiocarcinoma, colon adenocarcinoma, rectum adenocarcinoma, uterine corpus endometrial carcinoma, bladder urothelial carcinoma and breast cancer, while decreased in stomach adenocarcinoma, kidney renal clear cell carcinoma, prostate adenocarcinoma, lung squamous cell carcinoma, and esophageal carcinoma. PGA3, PGA4, and PGA5 were expressed in most normal tissues, but decreased in cancer tissues. PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer‐related pathways. PGC participated in 33 regulatory network pathways in pan‐cancer, mainly distributed in stomach adenocarcinoma, esophageal carcinoma, and lung squamous cell carcinoma, respectively. PGC and PGA3 expression were significantly correlated with immune cell infiltration. The results of survival analysis showed that different PGs expression play significantly different prognostic roles in different cancers. PGC was correlated with poor survival in brain lower grade glioma, skin cutaneous melanoma, and higher survival in kidney renal clear cell carcinoma, acute myeloid leukemia, mesothelioma, and uveal melanoma. PGA4 was only associated with higher survival in kidney renal clear cell carcinoma. Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types. PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased. Conclusions PGs was expressed unevenly in ...

Background: Here we carried out a panoramic analysis of the expression and prognosis of HSP110, HSP90, HSP70, and HSP60 families in 33 types of cancer, with the aim of deepening the systematic understanding of heat shock proteins (HSPs) in cancer.Materials and Methods: Next-generation sequencing data of multiple tumors were downloaded from TCGA, CCLE and Oncomine databases. RStudio 3.6.1 was used to analyze HSP110, HSP90, HSP70 and HSP60 families based on their expression in 33 types of cancer. The validations in vivo (stomach adenocarcinoma and colon adenocarcinoma tissues) were performed by qRT-PCR.Results: HSPs were differentially expressed in different cancers. The results revealed mainly positive correlations among the expressions of HSPs in different cancers. Expressions of HSP family members were generally associated with poor prognosis in respiratory, digestive, urinary and reproductive system tumors and associated with good prognosis in cholangiocarcinoma, pheochromocytoma and paraganglioma. TCGA mutation analysis showed that HSP gene mutation rate in cancers was 0–23%. CCLE mutation analysis indicated that HSP gene mutation rate in 828 cell lines from 15 tumors was 0–17%. CNV analysis revealed that HSPs have different degrees of gene amplifications and deletions in cancers. Gene mutations of 15 HSPs influenced their protein expressions in different cancers. Copy number amplifications and deletions of 22 HSPs also impacted protein expression levels in pan-cancer. HSP gene mutation was generally a poor prognosis factor in cancers, except for uterine corpus endometrial carcinoma. CNVs in 14 HSPs showed varying influences on survival status in different cancers. HSPs may be involved in the activation and inhibition of multiple cancer-related pathways. HSP expressions were closely correlated with 22 immune cell infiltrations in different cancers. The qRT-PCR validation results in vivo showed that HSPA2 was down-regulated in stomach adenocarcinoma and colon adenocarcinoma; HSPA7 and HSPA1A also were down-regulated in colon adenocarcinoma. HSPA2-HSPA7 (r = 0.031, p = 0.009) and HSPA1A-HSPA7 (r = 0.516, p < 0.001) were positive correlation in colon adenocarcinoma.Conclusion: These analysis and validation results show that HSP families play an important role in the occurrence and development of various tumors and are potential tumor diagnostic and prognostic biomarkers as well as anti-cancer therapeutic targets.