Su Lu

Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer.

Colon cancer is one of the most frequently diagnosed cancer and the third most fatal malignancy worldwide. HOTAIR, a cancer-associated long non-coding RNA (lncRNA), is a powerful biomarker of metastasis and poor prognosis in a diverse group of cancers. Nevertheless, an understanding of how HOTAIR is involved in colon cancer progression is limited. In the present study, we hypothesized that HOTAIR plays a crucial role in colon cancer development. We evaluated the expression of HOTAIR in 120 colon cancer samples, matched adjacent non-tumor mucosa and 32 lymph node metastasis tissues by real-time PCR. Increased HOTAIR expression was significantly correlated with the depth of tumor invasion, lymph node metastasis, organ metastasis, histological differentiation, vascular invasion and advanced tumor stage. Patients with high HOTAIR expression had higher recurrence rates and reduced metastasis-free and overall survival than patients with low HOTAIR expression. Moreover, our findings revealed that HOTAIR had a limited effect on cell proliferation but significantly promoted colon cancer cell migration and invasion in vitro. Depletion of HOTAIR increased the expression of E-cadherin while concomitantly decreasing expression of vimentin and MMP9. Hence, HOTAIR may be another pleiotropic modulator participating in epithelial-mesenchymal transition (EMT). These results indicate that HOTAIR may also be a valuable predictor for colon cancer management; furthermore, this lncRNA may be a potential target for cancer prevention and treatment.

Up-regulation of tripartite motif-containing 29 promotes cancer cell proliferation and predicts poor survival in colorectal cancer

Tripartite motif-containing 29 (TRIM29), also known as ataxia-telangiectasia group D, is structurally a member of the tripartite motif family of proteins, which characterized by the conserved RING finger, B-box, and coiled-coil domains. TRIM29 functions as an oncogene or a tumor suppressor depending on the tumor types. In this study, we aim to evaluate whether TRIM29 affects the tumorigenesis and progression of colorectal cancer. The expression of TRIM29 was investigated using real-time PCR in 40 pairs of colorectal cancer tissues and immunohistochemistry on a tissue microarray containing 203 cases of primary colorectal cancer paired with non-cancerous tissues. Down-regulation of TRIM29 was achieved by transient transfection in RKO cell lines, and the effects of TRIM29 on tumor proliferation were evaluated by MTT and plate colony formation assays. Results indicated that TRIM29 expression was much higher in colorectal cancer tissues and significantly associated with the depth of tumor invasion, lymph node metastasis, distant metastasis, histological differentiation, vascular invasion, ki-67 index, and advanced tumor stage. Patients with TRIM29-positive tumors had a higher recurrence rate and poorer survival than patients with TRIM29-negative tumors. In multivariate analyses, the TRIM29 expression was an independent factor for determining colorectal cancer prognosis after surgery. Moreover, down-regulation of TRIM29 inhibited tumor cell proliferation in vitro. In conclusion, TRIM29 plays an important role in promoting colorectal cancer progression. Our findings suggest that TRIM29 may serve as a novel biomarker for tumor recurrence and survival for colorectal cancer patients.

Overexpression of Reg4, alone or combined with MMP-7 overexpression, is predictive of poor prognosis in colorectal cancer.

Regenerating islet-derived family, member 4 (Reg4) is a secreted protein that plays a critical role in the development of colorectal cancer (CRC). In the present study, we examined the relationship between Reg4 and matrix metalloproteinase-7 (MMP-7) expression in CRC, particularly with regard to metastasis. RT-qPCR, western blotting, tissue microarray (TMA) and immunohistochemical staining were performed to detect Reg4 and MMP-7 expression in CRC tissues and paired adjacent normal tissues. As compared with normal tissues, most paired colon cancers showed a ≥2-fold increase in the Reg4 and MMP-7 mRNA levels, which was subsequently validated by the post-transcriptional levels. Immunohistochemical analysis demonstrated that Reg4 was associated with lymph node and distant metastasis, advanced American Joint Committee on Cancer (AJCC) stage, and histologic grade. Further studies showed the correlation between Reg4 and MMP-7 expression was significant in CRC with distant metastasis (r=0.555, P=0.021) and in the lymph‑node metastasis samples (r=0.557, P<0.001). Patients with tumor positivity for the two molecules showed a worse prognosis even after radical surgery (P<0.001). Multivariate analysis revealed that patients with Reg4- and MMP-7-positive tumors had extremely poor OS (HR 4.63; 95% CI 2.43-8.81; P<0.001) and DFS (HR 3.88; 95% CI 2.08-7.22; P<0.001). Reg4 expression may be useful in the prediction of colon cancer prognosis when combined with MMP-7.

Overexpression of HOXA10 promotes gastric cancer cells proliferation and HOXA10+/CD44+ is potential prognostic biomarker for gastric cancer

Gastric cancer (GC) is a malignant cancer with poor prognosis. This study aims to investigate the roles of homeobox A10 (HOXA10) in GC and the correlations between HOXA10/CD44 expression and GC prognosis. Based on qRT-PCR and Western Blot analyses in 50 pairs of fresh GC samples and adjacent normal samples, it is identified that HOXA10 was significantly up-regulated in GC tissues at mRNA and protein levels. Cell proliferation, migration, and invasion were enhanced in GC cells with overexpressed HOXA10, while inhibited in cells with silenced HOXA10. Through IPA software, HOXA10 was predicted to interact with CD44 via MSN, which was preliminarily confirmed by using Western Blot. Through immunohistochemistry and tissue microarray (N=264), it is found that HOXA10 expression was significantly correlated with tumor size (P=0.011) and CD44 expression (P<0.001), while CD44 expression was significantly correlated with tumor size (P<0.001), depth of tumor invasion (P<0.001), lymph node metastasis (P<0.001), distant metastasis (P=0.001), UICC stage (P<0.001), histological differentiation (P<0.001), and HOXA10 expression (P<0.001). Additionally, the over-all survival and disease-free survival of HOXA10(+)/CD44(+) patients were dramatically decreased in comparison with that of HOXA10(+)/CD44(-), HOXA10(-)/CD44(+), or HOXA10(-)/CD44(-) patients (P<0.001), suggesting that the combinatory expression of HOXA10 and CD44 was correlated with poor GC prognosis. In conclusion, HOXA10 and CD44 might play roles in GC tumorigenesis, metastasis, and invasion. HOXA10(+)/CD44(+) expression might serve as a prognostic biomarker for GC, which needs more studies to validate.

Ubiquitin-like with PHD and ring finger domains 2 is a predictor of survival and a potential therapeutic target in colon cancer

In the present study, we investigated the expression of ubiquitin-like with PHD and ring finger domains 2 (UHRF2) in colon cancer and adjacent normal tissues and estimated the clinicopathological significance and predictive value of UHRF2 expression in colon cancer. Using quantitative real-time PCR, tissue microarray (TMA), western blot analysis and immunohistochemical staining, we evaluated UHRF2 mRNA and protein levels in tumor tissues and paired adjacent normal epithelium. We found that UHRF2 was upregulated at both the transcriptional and translational levels in tumor tissues. Immunohistochemical detection of UHRF2 on a TMA containing 203 paired specimens showed that increased cytoplasmic UHRF2 was significantly associated with clinical stage, depth of invasion, nodal involvement, tumor histologic grade and the presence of metastasis. Patients with UHRF2-positive tumors had a much lower disease-free survival [hazard ratio (HR) 9.511, P<0.001] and overall survival (HR 9.820, P<0.001). Univariate and multivariate analyses were performed to determine the correlation between these parameters and the clinical and pathological variables of the study population verifying that UHRF2 immunoreactivity emerged as an independent prognostic factor in the multivariate analysis. UHRF2 may contribute to the progression of colon carcinogenesis and function as a novel prognostic indicator after curative operation.

Elevated HOXA1 expression correlates with accelerated tumor cell proliferation and poor prognosis in gastric cancer partly via cyclin D1.

BackgroundHOXA1 is a member of the Homeobox gene family, which encodes a group of highly conserved transcription factors that are important in embryonic development. However, it has been reported that HOXA1 exhibits oncogenic properties in many malignancies. This study focused on the expression and clinical significance of HOXA1 in gastric cancer (GC).MethodsTo assess the mRNA and protein expression of HOXA1 and cyclin D1 in GC tissues, we utilized qRT-PCR and western blotting, respectively. The effects of HOXA1 on GC cell proliferation, migration, and invasion, as well as xenograft tumor formation and the cell cycle were investigated in our established stable HOXA1 knockdown GC cell lines. The protein expression of HOXA1 and cyclin D1 was examined by immunohistochemistry using GC tissue microarrays (TMA) to analyze their relationship on a histological level. The Kaplan-Meier method and cox proportional hazards model were used to analyze the relationship of HOXA1 and cyclin D1 expression with GC clinical outcomes.ResultsHOXA1 mRNA and protein expression were upregulated in GC tissues. Knockdown of HOXA1 in GC cells not only inhibited cell proliferation, migration, and invasion in vitro but also suppressed xenograft tumor formation in vivo. Moreover, HOXA1 knockdown induced changes in the cell cycle, and HOXA1 knockdown cells were arrested at the G1 phase, the number of cells in S phase was reduced, and the expression of cyclin D1 was decreased. In GC tissues, high cyclin D1 mRNA and protein expression were detected, and a significant correlation was found between the expression of HOXA1 and cyclin D1. Survival analysis indicated that HOXA1 and cyclin D1 expression were significantly associated with disease-free survival (DFS) and overall survival (OS). Interestingly, patients with tumors that were positive for HOXA1 and cyclin D1 expression showed worse prognosis. Multivariate analysis confirmed that the combination of HOXA1 and cyclin D1 was an independent prognostic indicator for OS and DFS.ConclusionOur data show that HOXA1 plays a crucial role in GC development and clinical prognosis. HOXA1, alone or combination with cyclin D1, may serve as a novel prognostic biomarker for GC.

Secernin-1 Contributes to Colon Cancer Progression through Enhancing Matrix Metalloproteinase-2/9 Exocytosis

Emerging evidence shows that exocytosis plays a key role in tumor development and metastasis. Secernin-1 (SCRN1) is a novel regulator of exocytosis. Our previous work identified SCRN1 as a tumor-associated gene by bioinformatics analysis of transcriptomes. In this study, we demonstrated the aberrant overexpression of SCRN1 at mRNA and protein level in colon cancer. We also revealed that overexpression of SCRN1 was significantly associated with the tumor development and poor prognosis. Experiments in vitro validated that SCRN1 may promote cancer cell proliferation and secretion of matrix metalloproteinase-2/9 (MMP-2/9) proteins to accelerate tumor progression.

The chromatin-remodeling enzyme BRG1 promotes colon cancer progression via positive regulation of WNT3A.

In this study, we aimed to elucidate the clinical significance and underlying mechanisms of BRG1 in colon cancer. In the clinical analysis, overexpression of BRG1 correlates with colon cancer progression in two cohorts (n = 191 and n = 75). Kaplan-Meier survival analysis revealed that BRG1 is a prognosis predictor for overall survival (P < 0.001) and disease-free survival (P = 0.001). Knocking down BRG1 expression significantly suppressed the proliferation and invasion in colon cancer cells. The expression pattern of WNT3A is consistent with BRG1 in colon cancer tissues and WNT3A expression was inhibited in BRG1 knockdown cells. In addition, restoring WNT3A expression rescues the inhibition of cell proliferation and invasion induced by BRG1. In this study, we demonstrate that BRG1 may contribute to colon cancer progression through upregulating WNT3A expression.

Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) was significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation.

HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5-FU resistance by a p53-dependent pathway

5‐FU‐based chemotherapy is recently most recommended as the first‐line treatment for gastric cancer (GC). However, 5‐FU resistance is common for many postoperative GC patients. Homeobox A13 (HOXA13) is a member of homeobox genes highly expressed in many human tumors. Its potential roles and mechanisms of resistance to 5‐FU in GC are poorly understood. In this study, we discovered that HOXA13 played an oncogenic role in vivo and in vitro. The patients with HOXA13 overexpression were closely related with poor prognosis and more prone to be resistant to 5‐FU. Moreover, dehydrogenase/reductase 2 (DHRS2) was identified as a downstream gene of HOXA13. HOXA13 played a role of carcinogenesis through directly down‐regulating DHRS2 to increase MDM2. Furthermore, HOXA13 conferred 5‐FU resistance through MRP1 by a p53‐dependent pathway. Therefore, HOXA13 might serve as a potential signature that recognized patients who were insensitive to 5‐FU, and timely recommended them to other chemotherapy regimens.