Inhibition of Interleukin-6-Induced Matrix Metalloproteinase-2 Expression and Invasive Ability of Lemon Peel Polyphenol Extract in Human Primary Colon Cancer Cells

Among matrix metalloproteinases (MMPs), MMP-9/2 are key enzymes involved in the proteolysis of extracellular matrices in the inflammatory process and in cancer. Since MMP-9/2 expression levels, activity, and secretion is up-regulated during inflammation in response to pro-inflammatory cytokines, such as interleukin-6 (IL-6), many efforts have been devoted to identifying factors that could inhibit the IL-6-induced MMP-9/2 expression. Up to now, several reports indicated that polyphenols from fruits and vegetables are among the major components of health promotion for their antioxidant properties and also for their anti-inflammatory and anti-cancer agents. Among plant derived polyphenols, lemon (Citrus limon) peel extract (LPE) shows anti-cancer properties in various cancer types. In our previous work, we demonstrated that LPE can reduce IL-6-induced migration/invasiveness and MMP-9/2 up-regulation in some gastric cancer cell lines. This study aims to exploit the anti-cancer properties of LPE using an in vitro system model of inflammation, consisting of IL-6-exposed human primary colon cancer cells. We first analyzed the effect of LPE on IL-6-induced cell migration and invasiveness by wound healing and Boyden chamber assay, respectively. The MMP-2 mRNA expression levels and gelatinolytic activity in the cell culture media were determined by q-PCR analysis and gelatin zymography, respectively, and finally, the effects of LPE on IL-6-induced JAK2/STAT3 signaling pathways have been investigated by Western blotting analysis. Our results show that LPE is able to inhibit the IL-6-dependent cell migration and invasiveness associated with the up-regulation of MMP-2 expression levels and that these effects are correlated to the STAT3 phosphorylation in human primary T88 and T93 colon cancer cells.

Identification of histone methyltransferase NSD2 as an important oncogenic gene in colorectal cancer

Colorectal cancer (CRC) is the second common cause of cancer-related human mortalities. Dysregulation of histone 3 (H3) methylation could lead to transcriptional activation of multiple oncogenes, which is closely associated with CRC tumorigenesis and progression. Nuclear receptor-binding SET Domain protein 2 (NSD2) is a key histone methyltransferase catalyzing histone H3 lysine 36 dimethylation (H3K36me2). Its expression, the potential functions, and molecular mechanisms in CRC are studied here. Gene Expression Profiling Interactive Analysis (GEPIA) bioinformatics results showed that the NSD2 mRNA expression is elevated in both colon cancers and rectal cancers. Furthermore, NSD2 mRNA and protein expression levels in local colon cancer tissues are significantly higher than those in matched surrounding normal tissues. In primary human colon cancer cells and established CRC cell lines, shRNA-induced silencing or CRISPR/Cas9-induced knockout of NSD2 inhibited cell viability, proliferation, cell cycle progression, migration, and invasion. Furthermore, NSD2 shRNA or knockout induced mitochondrial depolarization, DNA damage, and apoptosis in the primary and established CRC cells. Contrarily, ectopic NSD2 overexpression in primary colon cancer cells further enhanced cell proliferation, migration, and invasion. H3K36me2, expressions of multiple oncogenes (ADAM9, EGFR, Sox2, Bcl-2, SYK, and MET) and Akt activation were significantly decreased after NSD2 silencing or knockout in primary colon cancer cells. Their levels were however increased after ectopic NSD2 overexpression. A catalytic inactive NSD2 (Y1179A) also inhibited H3K36me2, multiple oncogenes expression, and Akt activation, as well as cell proliferation and migration in primary colon cancer cells. In vivo, intratumoral injection of adeno-associated virus (AAV)-packed NSD2 shRNA largely inhibited primary colon cancer cell xenograft growth in nude mice. Together, NSD2 exerted oncogenic functions in CRC and could be a promising therapeutic target.

Colon Cancer With Metastatic Involvement of the Thyroid Incidentally Found at Excision of Parathyroid Adenoma

Metastatic disease from primary colon cancer in the thyroid is rare. The authors have submitted such a case. What makes this case particularly unusual is that it was in a man. 80% of such cases are in women. It has been speculated that there may be a humoral component. What is even more unique in this case is that it was found during the workup of a symptomatic parathyroid adenoma. The diagnosis was confirmed with immunochemistry using markers Cytokeratin 20 (CK20), Cytokeratin 7 (CK7), and Thyroid Transcription Factor 1 (TTF-1) .

Preoperative Predictors of Lymph Node Metastasis in Colon Cancer

BackgroundLymph node metastasis (LNM) is a well-established prognostic factor for colon cancer. Preoperative LNM evaluation is relevant for planning colon cancer treatment. The aim of this study was to construct and evaluate a nomogram for predicting LNM in primary colon cancer according to pathological features.Patients and MethodsSix-hundred patients with clinicopathologically confirmed colon cancer (481 cases in the training set and 119 cases in the validation set) were enrolled in the Affiliated Cancer Hospital of Guangxi Medical University from January 2010 to December 2019. The expression of molecular markers (p53 and β-catenin) was determined by immunohistochemistry. Multivariate logistic regression was used to screen out independent risk factors, and a nomogram was established. The accuracy and discriminability of the nomogram were evaluated by consistency index and calibration curve.ResultsUnivariate logistic analysis revealed that LNM in colon cancer is significantly correlated (P <0.05) with tumor size, grading, stage, preoperative carcinoembryonic antigen (CEA) level, and peripheral nerve infiltration (PNI). Multivariate logistic regression analysis confirmed that CEA, grading, and PNI were independent prognostic factors of LNM (P <0.05). The nomogram for predicting LNM risk showed acceptable consistency and calibration capability in the training and validation sets.ConclusionsPreoperative CEA level, grading, and PNI were independent risk factor for LNM. Based on the present parameters, the constructed prediction model of LNM has potential application value.

Colorectal Metastasis from Ovarian Neoplasm Mimicking Primary Colon Cancer

Metastasis to the colon from another primary internal malignancy is an untypical and a seldom reported entity. Direct visualization during colonoscopy is considered the gold standard of diagnosis. Pathologic diagnosis with immunohistochemical staining is essential to differentiate primary colorectal malignancy from secondary metastasis to the colon. We, hereby, present a case of a 53-year-old female status-post resection of left-sided papillary serous ovarian neoplasm who presented 2 years later with a single rectosigmoid intraluminal ulcerative mass imitating a primary colon cancer. Biopsies of the mass were consistent with metastasis from her primary ovarian carcinoma. We believe this case is unique because of the rarity of ovarian cancer metastasizing to the colon intraluminally rather than through direct locoregional invasion. Furthermore, it highlights the importance of considering secondary metastasis in patients with previous history of another primary internal malignancy.

Atypical Cells in Peritoneal Cleft: A Pitfall in Diagnosis of Colorectal Adenocarcinoma

Atypical cells in peritoneal clefts are usually either reactive mesothelial cells or pT4 colonic adenocarcinoma in colon specimen removed for primary colon cancer. However, rarely if ever are these atypical cells metastasis from other primary visceral malignancy due to “sac-like” anatomic structure of this area. We present a case where these atypical cells were determined to be metastasis of gynecological origin by judicious use of immunohistochemical stains. A final diagnosis of serous tubal intraepithelial carcinoma of right fallopian tube was diagnosed only after total abdominal hysterectomy bilateral salpingo-oophorectomy. To our knowledge, this is the first report of a serous tubal intraepithelial carcinoma presenting as stage 4 colonic adenocarcinoma. The importance of this interesting case is 2-fold. It highlights the peritoneal cleft as an anatomic region not often recognized or discussed as well as tumor presentation in this region. In addition, this example stresses the need for additional mesothelial markers in addition to WT-1 workup of atypical mesothelial proliferation.

Rare Distal Metastasis of Endometrial Adenocarcinoma Impersonating as Primary Colon Cancer

An 89-year-old Caucasian female with a recent diagnosis of endometrial adenocarcinoma status post hysterectomy and acute deep vein thrombosis on anticoagulation presented with hematochezia. Colonoscopy revealed sigmoid colon stricture with the biopsy findings of metastatic endometrial adenocarcinoma based on positive immunohistochemistry staining for cytokeratin 7, paired box gene 8, and estrogen receptor. The oncologist referral was given to the patient for consideration of chemotherapy, but she decided to go with palliative care. Thus far, only 2 similar cases have been published in the literature. Our case exemplifies the potential for an unconventional pattern of metastasis of primary endometrial adenocarcinoma to the colon.