Serum microRNA Levels as a Biomarker for Diagnosing Non-Alcoholic Fatty Liver Disease in Chinese Colorectal Polyp Patients.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and its prevalence is increasing worldwide. It is reported that NAFLD is associated with colorectal polyps. Since identifying NAFLD in its early stages could prevent possible disease progression to cirrhosis and decrease the risk of HCC by early intervention, patients with colorectal polyp may thus be considered a target group for screening NAFLD. This study aimed to investigate the potential of serum microRNAs (miRNAs) in identifying NAFLD for colorectal polyp patients. Serum samples were collected from 141 colorectal polyp patients, of which 38 had NAFLD. The serum level of eight miRNAs was determined by quantitative PCR and delta Ct values of different miRNA pairs which were compared between NAFLD and control groups. A miRNA panel was formulated from candidate miRNA pairs by multiple linear regression model and ROC analysis was performed to evaluate its diagnostic potential for NAFLD. Compared to the control group, the NAFLD group showed significantly lower delta Ct values of miR-18a/miR-16 (6.141 vs. 7.374, p = 0.009), miR-25-3p/miR-16 (2.311 vs. 2.978, p = 0.003), miR-18a/miR-21-5p (4.367 vs. 5.081, p = 0.021) and miR-18a/miR-92a-3p (8.807 vs. 9.582, p = 0.020). A serum miRNA panel composed of these four miRNA pairs significantly identified NAFLD in colorectal polyp patients with an AUC value of 0.6584 (p = 0.004). The performance of the miRNA panel was further improved to an AUC value of 0.8337 (p < 0.0001) when polyp patients with other concurrent metabolic disorders were removed from the analysis. The serum miRNA panel is a potential diagnostic biomarker for screening NAFLD in colorectal polyp patients. This serum miRNA test could be performed for colorectal polyp patients for early diagnosis and for prevention of the disease from progressing into more advanced stages.

MiR-509-3p is oncogenic, targets the tumor suppressor PHLPP2, and functions as a novel tumor adjacent normal tissue based prognostic biomarker in colorectal cancer.

BACKGROUND: Recently the role of microRNAs has been explored immensely as novel regulators and potential biomarkers in several cancers. MiR-509-3p is one such miRNA that has been observed to show a mixed expression in different cancers, while it's expression and clinical relevance in colorectal cancer (CRC) has not yet been characterized. METHODS: We used quantitative PCR to evaluate the expression of miR-509-3p in fresh-frozen CRC tumor tissues and the corresponding tumor-adjacent normal (NAT) tissues from 103 patients. Subsequently, functional studies were performed to further interpret the role of the miRNA in CRC. RESULTS: MiR-509-3p was found to be overexpressed in CRC tissues in nearly 80% of cases and was associated with an aggressive disease presentation. Notably, a higher expression of the miRNA promoted cell proliferation, migration, and invasion of CRC cells in in vitro and in vivo models. Mechanistically, we confirmed that miR-509-3p directly binds the 3'UTR of the tumor suppressor PHLPP2 and inhibits its expression. Furthermore, within the previous 103 clinical tissue specimens, we observed an overexpression of miR-509-3p within the NAT tissue of patients associated with a poor disease prognosis. Using multivariate analysis, it was observed that the expression of miR-509-3p within the NAT tissue was an independent predictor of prognosis in CRC. At the cellular level, through indirect coculture experiments, miR-509-3p was observed to regulate the proliferative, migratory, and invasive behavior of normal colon cells. CONCLUSION: MiR-509-3p strongly contributes to the development and progression of CRC and can potentially function as a prognostic biomarker in the disease.

CD26 Induces Colorectal Cancer Angiogenesis and Metastasis through CAV1/MMP1 Signaling.

CD26 has been reported as a marker for colorectal cancer stem cells endowed with tumor-initiating properties and capable of colorectal cancer (CRC) metastasis. In this study, we investigated the functional effect of CD26 on CRC angiogenesis and metastasis, and the potential underlying mechanism. The functional effects of CD26 overexpression or repression were determined by a wound healing experiment, and cell migration and invasion assays in vitro and in mouse models. Differentially expressed genes regulated by CD26 were identified by genome-wide mRNA expression array and validated by quantitative PCR. CD26 functionally regulated CRC cell migration and invasion in vitro and angiogenesis and metastasis in vivo. Genome-wide mRNA expression array and qPCR showed that MMP1 was up-regulated in CD26+ subpopulation, and a subsequent experiment demonstrated the regulatory effect of CD26 on MMP1 in CRC cell lines with CD26 repression or overexpression. Furthermore, overexpression of CAV1 abrogated the CD26-regulated MMP1 induction in CRC cell lines. This study demonstrated the functional roles of CD26 in inducing CRC migration, invasion, angiogenesis and metastasis and identified the potential involvement of MMP1 and CAV1 in such process. CD26 is an attractive therapeutic target for combating tumor progression to improve the prognosis of CRC patients.

Repurposing sodium-glucose co-transporter 2 inhibitors (SGLT2i) for cancer treatment - A Review.

Developed as an antidiabetic drug, recent evidence suggests that several sodium-glucose co-transporter 2 inhibitors (SGLT2i), especially canagliflozin and dapagliflozin, may exhibit in vitro and in vivo anticancer activities in selected cancer types, including an inhibition of tumor growth and induction of cell death. When used in combination with chemotherapy or radiotherapy, SGLT2i may offer possible synergistic effects in enhancing their treatment efficacy while alleviating associated side effects. Potential mechanisms include a reduction of glucose uptake into cancer cells, systemic glucose restriction, modulation of multiple signaling pathways, and regulation of different gene and protein expression. Furthermore, preliminary clinical findings have reported potential anticancer properties of canagliflozin and dapagliflozin in patients with liver and colon cancers respectively, with reference to decreases in their tumor marker levels. Given its general tolerability and routine use in diabetes management, SGLT2i may be a good candidate for drug repurposing in cancer treatment and as adjunct to conventional therapies. While current evidence reveals that only certain SGLT2i appear to be effective against selected cancer types, further studies are needed to explore the antitumor abilities of each SGLT2i in various cancers. Moreover, clinical trials are called for to evaluate the safety and feasibility of introducing SGLT2i in the treatment regimen of patients with specific cancers, and to identify the preferred route of drug administration for targeted delivery to selected tumor sites.

Overexpression of Pin1 and rho signaling partners correlates with metastatic behavior and poor recurrence-free survival of hepatocellular carcinoma patients.

BACKGROUND: Identification of molecular markers for early detection or prediction of metastasis is crucial for both management of HCC patient postoperative treatment and identify new therapeutic targets to inhibit HCC progression and metastasis. In the current study, we investigated the clinical correlation between Pin1, RhoA and RhoC and their association with HCC metastasis. METHODS: Using a randomized study design of primary HCC samples from 139 patients, we determined messenger RNA expression of Pin1, RhoA and RhoC and their prognostic value. RESULTS: Our findings demonstrated for the first time the clinical correlation of Pin1 in HCC metastasis. Pin1, RhoA and RhoC transcript levels were significantly higher in HCC specimens when compared with the paired adjacent non-tumorous liver. Pin1 overexpression was closely correlated with that of RhoA (R = 0.562, p < 0.001) and RhoC (R = 0.529, p < 0.001), and their co-overexpressions correlated with metastatic HCC (p = 0.000012) and poor recurrence-free survival of HCC patients (p < 0.00001), which showed better prognostic significance than either Pin1, RhoA or RhoC overexpression alone. Co-overexpressions of Pin1 + RhoA/RhoC were also an independent factor for predicting development of metastasis after curative resection in our multivariate regression model (p < 0.001). CONCLUSION: Pin1, RhoA and RhoC co-overexpressions are prognostic factor for metastatic HCC and predict poor recurrence-free survival.

Suppression of Slit3 induces tumor proliferation and chemoresistance in hepatocellular carcinoma through activation of GSK3ß/ß-catenin pathway.

BACKGROUND: It is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly. METHODS: We determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N = 40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models. RESULTS: Our results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of ß-catenin and a repressed GSK3ß activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of ß-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of ß-catenin by siRNA approach. CONCLUSION: This study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.

Emergence of CD26+ Cancer Stem Cells with Metastatic Properties in Colorectal Carcinogenesis.

Colorectal cancer results from genetic aberrations which accumulate over a long period of time, with malignant and metastatic properties acquired at a relatively late stage. A subpopulation of CD26+ colorectal cancer stem cells are known to be implicated in metastasis. We quantified CD26+ cancer cells in 11 primary tumor samples by flow cytometry, and showed that tumors having confirmed or suspected metastases harbored a relatively high CD26+ level in these samples. We hypothesized that this subpopulation of cancer stem cells arises in the late stage of carcinogenesis from the bulk of tumor daughter cells which are CD26-. The manipulation of PIK3CA and TP53, two genes commonly deregulated in the late stage, had an effect on the maintenance of the CD26+ cell population. When CD26- tumor daughter cells were sorted and cultured, the emergence of tumor spheres containing CD26+ cells occurred. These findings shed light to the origin of colorectal cancer stem cells with metastatic properties, which has an implication on conventional treatments by surgery or adjuvant chemotherapy for tumor debulking.

Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma.

BACKGROUND: In colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26(+) cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26(+) CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26(+) CSCs in CRC patients. METHODS: HT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26(+) CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model. RESULTS: Raf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26(+) cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated. CONCLUSIONS: This preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.

Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion.

UNLABELLED: Early reports suggested that actopaxin, a member of the focal adhesion proteins, regulates cell migration. Here we investigated whether actopaxin is involved in hepatocellular carcinoma (HCC) progression and metastasis. We examined actopaxin expression in human HCC samples using immunohistochemistry and western blotting. The functional and molecular effect of actopaxin was studied in vitro by overexpression in a nonmetastatic HCC cell line, as well as repression in a metastatic cell line. The in vivo effect of actopaxin repression was studied in nonobese diabetic and severe combined immunodeficient mice. We found that actopaxin was frequently overexpressed in human HCC patients and its overexpression positively correlated with tumor size, stage, and metastasis. Actopaxin expression also correlated with the metastatic potential of HCC cell lines. Actopaxin overexpression induced the invasion and migration ability of nonmetastatic HCC cells, whereas down-regulation of actopaxin reverted the invasive phenotypes and metastatic potential of metastatic HCC cells through regulating the protein expression of certain focal adhesion proteins including ILK, PINCH, paxillin, and cdc42, as well as regulating the epithelial-mesenchymal transition pathway. Furthermore, there was a close association between actopaxin and CD29. HCC cells with stronger CD29 expression showed a higher actopaxin level, whereas actopaxin repression attenuated CD29 activity. Finally, actopaxin down-regulation enhanced the chemosensitivity of HCC cells towards oxaliplatin treatment by way of a collective result of suppression of survivin protein, ß-catenin, and mammalian target of rapamycin pathways and up-regulation of p53. CONCLUSION: This study provides concrete evidence of a significant role of actopaxin in HCC progression and metastasis, by way of regulation of cell invasiveness and motility, an epithelial-mesenchymal transition process, and chemosensitivity to cytotoxic drugs.

Biomarkers for predicting future metastasis of human gastrointestinal tumors.

The recent advances in surgery and radiation therapy have significantly improved the prognosis of patients with primary cancer, and the major challenge of cancer treatment now is metastatic disease development. The 5-year survival rate of cancer patients who have distant metastasis at diagnosis is extremely low, suggesting that prediction and early detection of metastasis would definitely improve their prognosis because suitable patient therapeutic management and treatment strategy can be provided. Cancer cells from a primary site give rise to a metastatic tumor via a number of steps which require the involvement and altered expression of many regulators. These regulators may serve as biomarkers for predicting metastasis. Over the past few years, numerous regulators have been found correlating with metastasis. In this review, we summarize the findings of a number of potential biomarkers that are involved in cadherin-catenin interaction, integrin signaling, PI3K/Akt/mTOR signaling and cancer stem cell identification in gastrointestinal cancers. We will also discuss how certain biomarkers are associated with the tumor microenvironment that favors cancer metastasis.

Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells.

BACKGROUND: Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy. METHODS: We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo. RESULTS: Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery. CONCLUSIONS: Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.

A Four-Gene Panel in Rectal Swab Samples as a Biomarker for Colorectal Cancer Screening.

BACKGROUND: The dysregulation of gene expression is one of the key molecular features of colorectal cancer (CRC) development. This study aimed to investigate whether such dysregulation is reflected in rectal swab specimens of CRC patients and to evaluate its potential as a non-invasive approach for screening. METHODS: We compared the expression level of 14 CRC-associated genes in tumor and adjacent non-tumor tissue of CRC patients and examined the correlation of their levels in tissue with paired rectal swab specimens. The level of these 14 genes in rectal swab specimens was compared among patients with CRC or polyp and control subjects, and the diagnostic potential of each dysregulated gene and the gene panel were evaluated. RESULTS: The expression of CXCR2, SAA, COX1, PPARδ, PPARγ, Groγ, IL8, p21, c-myc, CD44 and CSF1 was significantly higher in CRC, and there was a significant correlation in the levels of most of them between the CRC and rectal swab specimens. In the training study, we showed that CD44, IL8, CXCR2 and c-myc levels were significantly higher in the rectal swab specimens of the CRC patients. Such result was confirmed in the validation study. A panel of these four genes was developed, and ROC analysis showed that this four-gene panel could identify CRC patients with an AUC value of 0.83 and identify overall polyp and precancerous adenoma patients with AUC values of 0.6522 and 0.7322, respectively. Finally, the predictive study showed that the four-gene panel demonstrated sensitivities of 63.6%, 76.9% and 88.9% in identifying overall polyp, precancerous adenoma and CRC patients, respectively, whereas the specificity for normal subjects was 72.2%. CONCLUSION: The expression of CRC-associated genes in rectal swab specimens reflects the dysregulation status in colorectal tissue, and the four-gene panel is a potential non-invasive biomarker for early precancerous adenoma and CRC screening.

Identification of CD44+ cancer stem cells in human gastric cancer.

The cancer stem cell hypothesis suggests that tumors are initiated and maintained by cancer stem cells capable of self-renewal and differentiation into mature tumor cells. Recent studies have demonstrated the existence of cancer initiating cells in different solid tumors. In this study, we identified a subpopulation of CD44+ cells within the tumor of gastric cancer patients, which, upon treatment by chemotherapeutic agent 5-fluorouracil (5-FU), were markedly enriched. In vitro culture of isolated CD44+ subpopulation from gastric tumors by magnetic beads sorting led to formation of gastric spheroid colonies. These colonies retained CD44+ surface marker expression during culture, and were undifferentiated in nature. Subcutaneous injections of CD44+ gastric cancer cells conferred tumorigenicity in SCID mice. Moreover, implantation of CD44+ cells from these established tumors remained tumorigenic in successive passages. Using CD44+ cells isolated from the gastric cell lines AGS and SGC7901, similar results were obtained. Upon enrichment by 5-FU, CD44+ cells harbored increased ALDH expression as compared with CD44- cells. Our results demonstrated for the first time the existence of CD44+ cells within the tumors of gastric cancer patients that are endowed with stem cells properties, and also provide a plausible explanation for chemo-resistance frequently observed in gastric cancer patients. Such findings provide a basis for further studies on targeting this tumorigenic subpopulation for better treatment of gastric cancer patients.

High Expression of a Cancer Stemness-Related Gene, Chromobox 8 (CBX8), in Normal Tissue Adjacent to the Tumor (NAT) Is Associated with Poor Prognosis of Colorectal Cancer Patients.

BACKGROUND: Several studies have demonstrated that the molecular profile of normal tissue adjacent to the tumor (NAT) is prognostic for recurrence in patients with different cancers. This study investigated the clinical significance of CBX8 gene expression, a cancer stemness-related gene, in tumor and NAT tissue of colorectal cancer (CRC) patients. METHODS: The gene level of CBX8 in paired CRC and NAT specimens from 95 patients was determined by quantitative PCR. CBX8 protein level in CRC and NAT specimens from 66 patients was determined by immunohistochemistry. CBX8 gene and protein levels were correlated with the patients' clinicopathological parameters and circulatory immune cell profiles. The association between CBX8 and pluripotency-associated genes was analyzed using the TCGA database. RESULTS: NAT CBX8 gene level positively correlated with TNM stage, tumor invasion, lymph node metastasis and distant metastasis, indicating its association with tumor progression and metastasis. There was no correlation between NAT CBX8 protein level and clinicopathological parameters. Moreover, a high level of CBX8 gene and protein in NAT both correlated with poor DFS and OS. There was an inverse correlation between CBX8 gene level and post-operative platelet counts and platelet to lymphocyte level, suggesting its association with systematic inflammation. Finally, TCGA analysis showed that CBX8 level was correlated with a couple of pluripotency-associated genes, supporting its association with cancer stemness. CONCLUSIONS: High NAT CBX8 is a poor prognostic factor for tumor progression and survival in CRC patients.

Investigation of miRNA dysregulation and association with immune cell profile during malignant transformation of colorectal cells.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent and life-threatening cancer among the world. Accumulated somatic mutations during malignant transformation process endow cancer cells with increased growth, invasiveness and immunogenicity. These highly immunogenic cancer cells develop multiple strategies to evade immune attack. Through post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer development and progression but also manipulate anti-cancer immune response. This study aims to identify miRNAs associated with the colorectal cell malignant transformation process and their association with immune cell population using synchronous adjacent normal, polyp and CRC specimens. METHODS: We conducted a Low Density Array to compare the miRNA expression profile of synchronous colorectal adenoma, adenocarcinoma and adjacent normal colon mucosa collected from 8 patients, in order to identify candidate miRNAs involved in CRC progression. These findings were further validated in 14 additional patients and GEO dataset GSE41655. The relative abundance of dendritic cells, natural killer cells, neutrophil and macrophage was determined and correlated with dysregulated miRNA levels. RESULTS: MicroRNA microarray identified 39 miRNAs aberrantly expressed during the colorectal cell transformation process. Seven novel miRNAs were shortlisted, and dysregulation of miR-149-3p, miR-192-3p, miR-335-5p and miR-425 were further validated by the qPCR validation experiment and data retrieved from the GEO dataset. Furthermore, these miRNAs demonstrated certain associations with level of dendritic cells, natural killer cells, neutrophil and macrophage within the polyp or CRC specimens. CONCLUSION: This study revealed miRNA dysregulated during stepwise malignant transformation of colorectal mucosal cells and their association with immune cell population.

High Levels of Tumor miR-187-3p-A Potential Tumor-Suppressor microRNA-Are Correlated with Poor Prognosis in Colorectal Cancer.

BACKGROUND: The microRNA miR-187-3p plays antitumor roles in a variety of cancers. We and others have previously identified miR-187-3p as a potential tumor suppressor in colorectal cancer (CRC), but there are also reports revealing that high miR-187-3p levels are associated with poor prognosis among CRC patients. This study further investigated the clinicopathological significance of miR-187-3p in CRC. METHODS: MiR-187-3p levels in paired polyp/CRC/normal specimens or primary CRC/liver metastasis specimens were determined by qPCR, and correlated with the patient's clinicopathological and postoperative survival data. The clinical findings were validated using our validation cohort and data obtained from the TCGA or GEO databases. The functional effects of miR-187-3p were investigated through its overexpression in CRC cell lines. RESULTS: MiR-187-3p was significantly repressed in colorectal polyps and CRC when compared to adjacent normal tissue. Overexpression of miR-187-3p in CRC cell lines impaired colony formation, cell migration, and invasion, and induced chemosensitivity. Clinical analysis revealed that despite miR-187-3p being repressed in CRC, high tumor miR-187-3p levels were positively correlated with tumor stage and disease recurrence. Further analysis showed that miR-187-3p levels were lower in metastatic specimens when compared to paired primary CRC, suggesting that high tumor miR-187-3p levels resulted from the dissemination of metastatic tumor cells. Tumor miR-187-3p levels were positively correlated with peripheral inflammation-related blood markers. Finally, SPRY1 was identified as a novel target gene of miR-187-3p, and was involved in miR-187-3p-impaired CRC metastasis. CONCLUSIONS: This study demonstrated that in spite of its repression and role as a tumor suppressor in CRC, high levels of miR-187-3p in tumors were correlated with poor prognosis and higher levels of peripheral inflammation-related blood markers.

Repurposing DPP-4 Inhibitors for Colorectal Cancer: A Retrospective and Single Center Study.

BACKGROUND: There have been studies reporting the crucial roles of Dipeptidyl-peptidase 4 (DPP4) in colorectal cancer (CRC) initiation and progression, whereas DPP4-inhibitors are safe Food and Drug Association (FDA)-approved drugs for treating diabetes. This study aims to investigate the association between DPP4-inhibitor treatment and the prognosis of CRC patients. METHODS: Clinical data of CRC patients with diabetes and the prescription of DPP4-inhibitors who had undergone curative surgery in our hospital between January 2006 and December 2015 were retrieved. Their survival data and immune cell population in circulatory blood were compared to those treated with metformin. RESULTS: The DPP4-inhibitor patient group showed a significantly better 5-year disease-free survival (median DFS = 1733 days, 95% CI = 1596 to 1870 days) when compared to the metformin group (p = 0.030, median DFS = 1382 days, 95% CI = 1246 to 1518 days). 33 out of the 92 patients in the metformin group showed recurrence whereas only 3 of the 26 patients in the DPP4-inhibitor group showed recurrence (p = 0.033). Cox regression analysis demonstrated that DPP4-inhibitor application is a favorable factor associated with a lower risk of recurrence (Hazard ratio = 0.200, p = 0.035). Furthermore, our results suggested that the immune cell profile of CRC patients is a potential biomarker for response to DPP4-inhibitor treatment. CONCLUSION: This study demonstrated the association of DPP4-inhibitor treatment with a better prognosis of CRC patients.

Application of droplet digital polymerase chain reaction of plasma methylated septin 9 on detection and early monitoring of colorectal cancer.

Methylated septin 9 (SEPT9) has been approved for non-invasive screening of colorectal cancer (CRC), but data on monitoring of CRC is sparse. Droplet digital polymerase chain reaction (ddPCR), with higher detection precision and simpler quantification than conventional PCR, has not been applied in SEPT9 detection. We explored the role of SEPT9 ddPCR for CRC detection and to measure serial SEPT9 levels in blood samples of CRC patients before and 3-month after surgery. SEPT9 methylated ratio, methylated abundance, and CEA levels were all higher in CRC patients than normal controls (all P < 0.05). The area under the curve (AUC) for methylated ratio and abundance to detect CRC was 0.707 and 0.710, respectively. There was an increasing trend for SEPT9 methylated abundance from proximal to distal cancers (P = 0.017). At 3-month after surgery, both methylated abundance and ratio decreased (P = 0.005 and 0.053, respectively), especially methylated abundance in stage III and distal cancer (both P < 0.01). We have developed a ddPCR platform for the quantitative detection of plasma SEPT9 in CRC patients. SEPT9 methylated abundance had an early post-operative decline, which may be useful in monitoring of treatment response.

A Pilot Study Investigating the Expression Levels of Pluripotency-Associated Genes in Rectal Swab Samples for Colorectal Polyp and Cancer Diagnosis and Prognosis.

Change in gene expression is inevitable in cancer development. With more studies demonstrating the contributions of cancer stem cells (CSCs) in colorectal cancer (CRC) development, this study is aimed at investigating whether rectal swab specimen serves as a tool for detection of dysregulation of CSC or stem cell (SC) markers and at evaluating its potential as a new promising screening method for high-risk patients. Expression levels of 15 pluripotency-associated genes were assessed by quantitative PCR in 53 rectal swab specimens referred for endoscopic screening. Dysregulated genes and joint panels based on such genes were examined for their diagnostic potentials for both polyp and CRC. Out of 15 genes, Oct4, CD26, c-MYC, and CXCR4 showed significantly differential expression among normal, polyp, and CRC patients. A panel of Oct4 and CD26 showed an AUC value of 0.80 (p = 0.003) in identifying CRC patients from polyp/normal subjects, with sensitivity and specificity of 84.6% and 69.2%. A panel of c-MYC and CXCR4 achieved CRC/polyp identification with an AUC value of 0.79 (p = 0.002), with a sensitivity of 82.8% and specificity of 80.0%. The sensitivity for polyp and CRC was 80.0% and 85.7%, respectively. Further analysis showed that higher c-MYC and CXCR4 level was detected in normal subjects who developed polyps after 5-6 years, in comparison with subjects with no lesion developed, and the AUC of the c-MYC and CXCR4 panel increased to 0.88 (p < 0.001), with sensitivity and specificity of 84.4% and 92.3%, respectively, when these patients were included in the polyp group. This study suggests that the Oct4 and CD26 panel is a promising biomarker for distinguishing CRC from normal and polyp patients, whereas the c-MYC and CXCR4 panel may identify polyp and CRC from normal individuals.

Novel molecular targets in hepatocellular carcinoma.

Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.