The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology

Abstract Background The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. Results We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. Conclusion We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.

Tankyrase expression in lung bronchiolo-alveolar adenocarcinoma and its relationship with the WNT pathway / 天津医药

Objective To explore the expression of tankyrase (TNKS) and its relationship with WNT/β-catenin signal?ing pathway in lung acinar adenocarcinoma. Methods Seventy-two samples of single subtype alveolar like lung adenocarci?noma (lung adenocarcinoma group) and 67 specimens of normal lung tissue adjacent to carcinoma (adjacent to carcinoma group) were collected. Immunohistochemical method was used to detect expressions of TNKS, beta-catenin (β-catenin) and c-myc protein. The correlation of each protein expression in lung adenocarcinoma tissues was analyzed. The differential ex?pression of TNKS was detected by Western blot assay in two groups. Results Tankyrase protein was mainly expressed in cy?toplasm. The expression ofβ-catenin protein was mainly in cytoplasm and nuclear of lung adenocarcinoma. The expression ofβ-catenin was mainly in cytoplasm, and a small amount was in nuclear of the adjacent group. The c-myc protein was ex?pressed mainly in the nucleus. The positive expression rates of TNKS,β-catenin and c-myc protein were significantly high?er in lung adenocarcinoma group than those of adjacent to carcinoma group (P<0.05). The expression ofβ-catenin in cyto?plasm and nucleus was positively correlated with the expression of TNKS and c-myc (P<0.05). Western blot analysis showed that the relative expression level of TNKS was significantly higher in lung adenocarcinoma group than that of adja?cent to carcinoma group (0.497 ± 0.021 vs. 0.237 ± 0.015, t=13.00, P<0.01). Conclusion Abnormally high expression of TNKS in lung adenocarcinoma may promote the occurrence of lung cancer by regulating the WNT signaling pathways. Inhib?iting TNKS expression may become a new target to treat lung adenocarcinoma.

Telomere-associated factor expression in replicative senescence of human embryonic lung fibroblasts / 中国组织工程研究

BACKGROUND: Telomere-associated proteins wil directly affect the function of telomeres, adjust the length of telomeric DNA, which are closely related with cellsenescence and carcinogenesis. OBJECTIVE: To find the key regulatory molecules in the cellsenescence process through observing the telomere-associated factor expression in normal cel replicative senescence process. METHODS: Based on established cel replicative senescence model, reverse transcription-PCR and western blot were used to detect the telomere-associated factor expression on the molecular and protein levels, including the telomere-associated factor human telomere binding protein 1, tankyrase 1, telomerase RNA, telomere protection protein 1 and P53 expressions in the human embryonic lung fibroblast replicative senescence. RESULTS AND CONCLUSION: The results showed that with the cellsenescence, transcription of human telomere binding protein 1 did not changed, while the protein expression of human telomere binding protein 1 was increased gradual y and then decreased rapidly; mRNA and protein expressions of telomere protection protein 1 did not changed; with the human embryonic lung fibroblast replicative senescence, expression of telomere protection protein 1 was decreased gradual y; with cellsenescence, telomerase RNA component showed an increasing trend; protein expression of P53 did not changed. Human telomere binding protein 1, telomere protection protein 1 and telomerase RNA play an important role in cellsenescence.

Expression of telomere regulating factor tankyrase in gastric adenocarcinoma / 中国病理生理杂志

AIM: To detect the expression level of telomere regulating factor tankyrase and its clinical significance in the origin and development of gastric adenocarcinoma. METHODS: Quantitative Real-time PCR was used to measure the expression of tankyrase mRNA in cancerous and normal adjacent tissues from 16 patients with gastric adenocarcinoma. Immunohistochemistry was used to detect tankyrase protein expressions in 37 gastric adenocarcinoma samples and 13 normal controls. RESULTS: The expression of tankyrase mRNA in gastric adenocarcinoma [median 1.44?10~ -2, range (3.88?10~ -5)-0.4847] was significantly higher than that in normal adjacent mucosa [median 1.0134?10~ -2, range 0-(4.933?10~ -2)] (P