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Effect of CEACAM6 silencing on the biological behavior of human gallbladder cancer cells.

ABSTRACT: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is abnormally expressed in various malignant tumors and thus represents a potential biomarker, although information regarding its role in gallbladder cancer (GBC) is limited. This study aimed to evaluate the expression of CEACAM6 in GBC and the effect of CEACAM6 gene silencing on the proliferation, migration, invasion and apoptosis of human GBC cells. Immunochemistry was used to evaluate CEACAM6 expression in 95 GBC specimens and 40 peritumoral tissue specimens. GBC-SD and SGC-996 cell lines were used for in vitro experiments. CEACAM6 was knocked down by transfection of targeted small interfering RNA (siRNA), and reverse-transcription quantitative PCR and western blot analysis were used to detect knockdown efficiency. Cell Counting Kit-8 and colony formation assays were undertaken to evaluate cell proliferation. Variations in cell migration and invasion were detected by wound-healing and Transwell assays, respectively. Flow cytometry was applied to measure cell apoptosis and cell cycle distribution. CEACAM6 gene expression was significantly greater in GBC tissues than in peritumoral tissues, and its positive expression was associated with poor prognosis. CEACAM6 mRNA and protein expression in the CEACAM6 siRNA treatment group was significantly lower than that in the negative control group and the blank group. CEACAM6 knockdown inhibited GBC cell proliferation, migration and invasion but promoted cell apoptosis. Western blot analysis of invasion- and apoptosis-related proteins matrix metalloproteinase-2, Vimentin, BCL-2 and BAX further confirmed CEACAM6 mRNA depletion promoted cell apoptosis and inhibited invasion. Additionally, CEACAM6 mRNA depletion affected the progression of the GBC cell cycle to increase cell distribution in G0/G1 phase, and to reduce it in G2/M phase and S phase. These findings indicated that CEACAM6 overexpression may be related to the tumorigenesis and development of GBC. In summary, depletion of CEACAM6 mRNA suppressed the malignant biological behaviors of human gallbladder cancer cells.

SUBMITTER: Tian C

PROVIDER: S-EPMC7400980 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Effect of CEACAM6 silencing on the biological behavior of human gallbladder cancer cells.

Tian Chengming C Zhang Bingye B Ge Chunlin C

Oncology letters 20200703 3

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is abnormally expressed in various malignant tumors and thus represents a potential biomarker, although information regarding its role in gallbladder cancer (GBC) is limited. This study aimed to evaluate the expression of CEACAM6 in GBC and the effect of CEACAM6 gene silencing on the proliferation, migration, invasion and apoptosis of human GBC cells. Immunochemistry was used to evaluate CEACAM6 expression in 95 GB ...[more]

PMID: 32782584

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Project description:Carcinoma of the gallbladder (GBC) is the most frequent tumor of the biliary tract. Despite epidemiological studies showing a correlation between chronic infection with Salmonella enterica Typhi/Paratyphi A and GBC, the underlying molecular mechanisms of this fatal connection are still uncertain. The murine serovar Salmonella Typhimurium has been shown to promote transformation of genetically predisposed cells by driving mitogenic signaling. However, insights from this strain remain limited as it lacks the typhoid toxin produced by the human serovars Typhi and Paratyphi A. In particular, the CdtB subunit of the typhoid toxin directly induces DNA breaks in host cells, likely promoting transformation. To assess the underlying principles of transformation, we used gallbladder organoids as an infection model for Salmonella Paratyphi A. In this model, bacteria can invade epithelial cells, and we observed host cell DNA damage. The induction of DNA double-strand breaks after infection depended on the typhoid toxin CdtB subunit and extended to neighboring, non-infected cells. By cultivating the organoid derived cells into polarized monolayers in air-liquid interphase, we could extend the duration of the infection, and we observed an initial arrest of the cell cycle that does not depend on the typhoid toxin. Non-infected intoxicated cells instead continued to proliferate despite the DNA damage. Our study highlights the importance of the typhoid toxin in causing genomic instability and corroborates the epidemiological link between Salmonella infection and GBC.IMPORTANCE Bacterial infections are increasingly being recognized as risk factors for the development of adenocarcinomas. The strong epidemiological evidence linking Helicobacter pylori infection to stomach cancer has paved the way to the demonstration that bacterial infections cause DNA damage in the host cells, initiating transformation. In this regard, the role of bacterial genotoxins has become more relevant. Salmonella enterica serovars Typhi and Paratyphi A have been clinically associated with gallbladder cancer. By harnessing the stem cell potential of cells from healthy human gallbladder explant, we regenerated and propagated the epithelium of this organ in vitro and used these cultures to model S. Paratyphi A infection. This study demonstrates the importance of the typhoid toxin, encoded only by these specific serovars, in causing genomic instability in healthy gallbladder cells, posing intoxicated cells at risk of malignant transformation.

Project description:BackgroundInositol polyphosphate 4-phosphatase type II (INPP4B) is a negative regulator of the PI3K-Akt signalling pathway and plays a contradictory role in different types of cancers. However, the its biological role played by INPP4B in human gallbladder cancer (GBC) has not been elucidated. In this study, we investigated the expression, clinical significance and biological function of INPP4B in GBC patients and cell lines.MethodsThe INPP4B protein expression levels in gallbladder cancer tissues and normal gallbladder tissues were detected by immunohistochemistry, and the clinical significance of INPP4B was analysed. Knockdown and overexpression of INPP4B in GBC-SD and SGC-996 cells followed by cell proliferation, clonogenic, apoptosis detection, scratch wound-healing and transwell assays were used to identify INPP4B function in vitro.ResultsINPP4B was up-regulated in human GBC tissues compared with normal gallbladder tissues and was related to histopathological differentiation (p = 0.026). Here, we observed that INPP4B was highly expressed in high-moderately differentiated tumours compared with low-undifferentiated tumours (p = 0.022). Additionally, we found that INPP4B expression was not associated with overall survival of GBC patients (p = 0.071) and was not an independent prognostic factor. Furthermore, when we stratified the relationship between INPP4B expression and the prognosis of GBC based on histopathological differentiation, we found that INPP4B played a contradictory role in GBC progression depending on the degree of differentiation. In addition, INPP4B knockdown inhibited the proliferation, colony formation, migration and invasion in GBC cells, while INPP4B overexpression had the opposite effects in vitro, which indicates its role as an oncoprotein.ConclusionsThese findings suggested that INPP4B may play a dual role in the prognosis of GBC depending on the degree of differentiation and that INPP4B might act as an oncogene in gallbladder cancer cells.

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Effect of CEACAM6 silencing on the biological behavior of human gallbladder cancer cells.

Publications

Effect of <i>CEACAM6</i> silencing on the biological behavior of human gallbladder cancer cells.

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