Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis
Chuangen LiYong WangDabin LiuChi Chun WongOlabisi Oluwabukola CokerXiang ZhangChangan LiuYunfei ZhouYali LiuWei KangKa‐Fai ToJoseph J.�Y. SungJun Yu
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Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis.Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses.SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth.This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.Keywords:
Squalene monooxygenase
Colorectal cancer (CRC) is a leading cause of cancer-related death around the world whose recurrence and metastasis rate is high. Due to the underlying unclear pathogenesis, it is hard so far to predict the tumorigenesis and prevent its recurrence. YAP/TAZ has been reported to be activated and functioned as a potential oncogene in multiple cancer types and proved to be essential for the carcinogenesis of most solid tumors. In the present study, we found that YAP/TAZ was markedly upregulated in CRC tissues comparing with the adjacent noncancerous tissues due to the downregulation of LATS2, the main upstream regulator. We further identified miR-429 as a direct regulator of LATS2-YAP/TAZ activation, suggesting that the miR-429-LATS2-YAP/TAZ might be novel effective diagnostic axis and therapeutic targets for CRC.
Pathogenesis
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Prostate cancer (PCa) is a destructive malignancy with a bad prognosis. LncRNA VPS9D1-AS1 has recently been delineated as an oncogene in some kinds of tumor, whereas, the function of VPS9D1-AS1 in PCa remains to be clarified. In this study, we researched its underlying role in PCa. The expression of VPS9D1-AS1 was conspicuously upregulated in PCa tissues and cells. And absence of VPS9D1-AS1 inhibited cell proliferation, migration and invasion, and promoted cell apoptosis in PCa. In addition, VPS9D1-AS1 overexpression led to opposite results. Furthermore, VPS9D1-AS1/MEF2D could sponge with miR-4739. VPS9D1-AS1/MEF2D and miR-4739 were inversely correlated in tumor cells. And the expression of miR-4739 is markedly downregulated in PCa, meanwhile, that of MEF2D exhibited the opposite tendency. However, MEF2D was positively regulated by VPS9D1-AS1. Moreover, MEF2D upregulation offset the suppressive effects of VPS9D1-AS1 deficiency on cell proliferation, migration and invasion in PCa. Additionally, ZEB1 contained the binding sites of VPS9D1-AS1 promoter, and there existed positive relation between them. Taken together, above results illustrated that ZEB1 activated-VPS9D1-AS1 promotes the tumorigenesis and progression of PCa by sponging miR-4739 to upregulate MEF2D, which offering a new useful reference for studying the development process of PCa.
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Prostate cancer (PCa) is the second frequently newly diagnosed cancer in men. Androgen deprivation therapy has been widely used to inhibit PCa growth but eventually fails in many patients. Androgen receptor and its downstream molecules like microRNAs could be promising therapeutic targets. We aimed to investigate the involvement of miR-21 in PCa tumorigenesis. We found that miR-21 was an unfavorable factor and correlated positively with tumor grade in PCa patients from TCGA database. MiR-21 was more highly expressed in androgen-independent PCa cells than in androgen-dependent PCa cells. Overexpression of miR-21 promoted androgen-dependent and -independent PCa cell proliferation, migration, invasion, and resistance to apoptosis. Furthermore, increased miR-21 expression promoted mouse xenograft growth. We identified nine genes differentially expressed in PCa tumors and normal tissue which could be potential targets of miR-21 by bioinformatic analyses. We demonstrate that miR-21 directly targeted KLF5 and inhibited KLF5 mRNA and protein levels in PCa. STRING and functional enrichment analysis results suggest that GSK3B might be regulated by KLF5. Our findings demonstrate that miR-21 promotes the tumorigenesis of PCa cells by directly targeting KLF5. These biological effects are mediated through upregulation of GSK3B and activation of the AKT signaling pathway.
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The DNA damage response helps to maintain genome integrity, suppress tumorigenesis, and mediate the effects of radiotherapy and chemotherapy. Our previous studies have shown that Smad1 is upregulated and activated by Atm in DNA damage response, which can further bind to p53 and promote p53 stabilization. Here we report another aspect of the interplay between p53 and Smad1. Comparison of rectal tumor against paired paraneoplastic specimens and analysis of >500 colorectal tumors revealed that Smad1 was upregulated in tumor samples, which was attributable to p53 defects. Using MEFs as a model, we found that knockdown of the elevated Smad1 in p53−/− MEFs promoted cell proliferation, E1A/Ras-induced cell transformation, and tumorigenesis. Mechanistic studies suggest that elevated Smad1 and momentary activation inhibit cell proliferation by upregulating p57Kip2 and enhancing Atm–Chk2 activation. Surprisingly, elevated Smad1 appears to have a negative effect on chemotherapy, as colorectal tumors, primary cancer cells, and cell lines with Smad1 knockdown all showed an increase in chemosensitivity, which could be attributable to elevated p57Kip2. These findings underscore the significance of Smad1–p53 interaction in tumor suppression and reveal an unexpected role for Smad1 in chemoresistance of colorectal cancers.
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Homeobox B7 (HOXB7), a member of the HOX gene family, plays a role in tumorigenesis. However, until now the expression status and role of HOXB7 in osteosarcoma remain unclear. Therefore, the present study aimed to investigate the functional role and mechanism of HOXB7 in osteosarcoma. Our results demonstrated that HOXB7 was overexpressed in osteosarcoma cell lines. Downregulation of HOXB7 significantly inhibited osteosarcoma cell proliferation in vitro, as well as attenuated xenograft tumor growth in vivo. Downregulation of HOXB7 also inhibited the migration and invasion of osteosarcoma cells. Furthermore, downregulation of HOXB7 significantly suppressed the protein expression levels of p-PI3K and p-Akt in U2OS cells. In summary, our data demonstrated that downregulation of HOXB7 inhibited proliferation, invasion, and tumorigenesis, partly through suppressing the PI3K/Akt signaling pathway in osteosarcoma cells. Our findings provide new insights into the role of HOXB7 in osteosarcoma and new therapeutic targets for the treatment of osteosarcoma.
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Abstract Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide and is the second leading cause of cancer death in China. We have previously demonstrated that LAPTM4B‐35, encoded by lysosomal protein transmembrane 4 beta gene , is overexpressed in over 80% of HCCs and is a novel‐independent prognostic factor for metastasis, recurrence, and postoperative survival in HCC. In this study, we investigated the role of LAPTM4B‐35 in malignant transformation and tumorigenesis using L02 cells, a cell line originated from human normal liver cells. Our data show that replication‐deficient adenovirus vector‐mediated upregulation of LAPTM4B‐35 promotes anchorage‐independent proliferation and resistance to adriamycin‐induced apoptosis. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included the activation of phosphoinositide 3‐kinases (PI3K)/serine/threonine protein kinase B (PKB/AKT)/bcl‐xL/bcl‐2‐associated death promoter homolog (Bad) signaling pathway, inhibition of caspase‐3 activation, upregulation of Bcl‐2, and downregulation of Bax. In addition, upregulation of LAPTM4B‐35 in L02 cells resulted in tumorigenesis in 100% (6/6) of inoculated nude mice and accelerated the death of mice with xenografts in vivo . In conclusion, LAPTM4B‐35 promotes malignant transformation and tumorigenesis in human liver L02 cell line through promotion of deregulated proliferation and inhibition of apoptosis. These findings suggest that overexpression of LAPTM4B‐35 may play a critical role in hepatocarcinogenesis and therefore, may be a therapeutic target for HCC. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.
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HCCS
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Accumulating evidence has indicated that, aberrant lncRNA expression plays essential roles in the colorectal cancer (CRC) tumorigenesis. AGAP2-AS1 is upregulated in some cancers, however, its involvement in the CRC tumorigenesis in the population of North-West of Iran has remained unknown. In this study, we evaluated its deregulation in CRC microarray datasets, colon cell lines, CRC tumor, adenomatous colorectal polyps and their paired normal tissues. The results showed that AGAP2-AS1 is upregulated in CRC and might be considered as a potential biomarker for CRC development. Moreover, our results suggest AGAP2-AS1 promoted CRC progression by sponging the hsa-miR-15/16 family and upregulation of their targets.
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Abstract Glioblastoma (GBM) is the most common malignancy tumor of central nervous system. PTBP3 was closely associated with the development of tumor. However, the function and mechanism of PTBP3 in GBM is little known. We found that PTBP3 was upregulated in GBM, and higher expression of PTBP3 corrected with the poor survival of GBM patients. Knockdown PTBP3 reduced proliferation, EMT, invasion, and migration of GBM. Conversely, overexpressing PTBP3 has an opposite effect. Moreover, we found that PTBP3 stabilized Twist1 by decreasing its ubiquitination and degradation. Furthermore, orthotopic xenograft models were used to demonstrate the PTBP3 on the development of GBM in vivo . This study proved that PTBP3 promoted tumorigenesis of GBM by stabilizing Twist1, which provided a new therapeutic target for GBM.
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Competing Endogenous RNA
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Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial for tumorigenesis. Previously, we have identified that miR-31 is frequently upregulated in OSCC and that this miR-31 increase, together with downstream effector modulation, enhances oral carcinogenesis. We have identified higher levels of miR-31 expression in oral potential malignant disorder (OPMD) tissues compared with normal oral mucosa. Exogenous miR-31 and human telomerase reverse transcriptase (hTERT) expression were introduced into cultured normal oral keratinocytes (NOKs), which led to the immortalization; these lines were designated M31OK1 and M31OK3. These immortalized lines maintained the capability to undergo squamous differentiation. In addition, migration by both cell lines was attenuated by hTERT and miR-31 knockdown. M31OK1 carries a p53 gene mutation at codon 273. A serum-tolerant subline, M31OK1-D, exhibits potent anchorage-independent growth that is attenuated by knockdown of both hTERT and miR-31. miR-31-targeted factors inhibiting HIF (FIH), which upregulated vascular endothelial growth factor (VEGF), was found crucial for oral tumorigenesis. The proliferation, migration and epithelial–mesenchymal transition of M31OK1-D are associated with downregulation of FIH and upregulation of VEGF, which require miR-31 expression. High miR-31 expression is correlated with higher VEGF expression and lower E-cadherin expression in OPMD tissue. It can be concluded that miR-31 collaborates with hTERT to immortalize NOKs and that this may contribute to early stage oral carcinogenesis. The targeting of downstream factors by miR-31 may further advance the neoplastic progression of immortalized NOKs, allowing them to become malignant.
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