Colorectal Cancer (CRC): Investigating the Expression of the Suppressor of Fused (SuFu) Gene and Its Relationship with Several Inflammatory Blood-Based Biomarkers.

BACKGROUND: Suppressor of fused (SuFu) is a tumor-suppressor gene that regulates hedgehog signaling. Its involvement in some malignancies is broadly accepted. However, its association with colorectal cancer (CRC) pathogenesis is not clear. Likewise, no study has clearly associated blood-based inflammatory biomarkers with cancer diagnosis/prognosis as yet. AIM: Our goal was to look at SuFu expression levels in CRC patients and its relationship with other clinicopathological factors. Additionally, we looked into the function of a few blood-based biomarkers in CRC and whether or not a combined strategy at the genetic and clinical levels can be applied in CRC. METHODS: The investigation included 98 histopathologically confirmed CRC samples and adjacent normal tissues (controls). A colonoscopy was followed by a targeted biopsy for each suspected colon cancer patient. A CT scan and MRI were also performed on every patient with rectal cancer. Real-time polymerase chain reaction and immunohistochemistry (IHC) were used for assessment. A Beckman Coulter DxH900 was used to examine blood parameters. A Beckman Coulter DxI800 was used to identify pretreatment carcinoma embryonic antigens (CEA) and carbohydrate antigens (CA 19-9) in CRC patients. RESULTS: The expression of SuFu was associated with gender, education, passive smoking, tumor grade, perineural invasion (PNI), lymph node metastasis (LNM), node status, stage, vital status, and recurrence (p < 0.05). In the combined analysis, the areas under the curve produced by the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and red cell distribution width (RDW) were the greatest (AUCRDW+PLR+NLR = 0.91, 95% CI: 0.86-0.93, p < 0.05). Furthermore, the most severe pathological features were linked to RDW, PLR, NLR, and HPR. SuFu expression, node status, LNM, PNI, and stage all had significant correlations with OS and DFS rates in IHC-based univariate survival analysis (p < 0.05). According to the Cox regression, CA-19.9 had a strong independent predictive link with 3-year DFS (p < 0.05). CONCLUSION: In CRC, SuFu was downregulated both transcriptionally and translationally, was primarily nucleo-cytoplasmic, and was expressed less in high-grade tumors. In addition, SuFu was linked to a poor overall and disease-free survival rate. It may be possible to use SuFu as a therapeutic target for CRC in the future. However, SuFu expression had no effect on RDW, PLR, NLR, or HPR serum levels.

Telomere Attrition With Concomitant hTERT Overexpression Involved in the Progression of Gastric Cancer May Have Prognostic and Clinical Implications in High-Risk Population Group From North India.

Genetic instabilities exacerbated by the dysfunction of telomeres can lead to the development of cancer. Nearly 90% of all human malignancies are linked with telomere dysregulation and overexpression of telomerase, an enzyme that catalyzes the synthesis of telomeric DNA repeats at the ends of chromosomes. The burden of gastric cancer continues to inflict a deterring impact on the global health scenario, accounting for over one million new cases in 2020. The disease is asymptomatic in its early stages of progression, which is attributed to the poor prognosis and overall surge in mortality rate worldwide. Exploiting telomere physiology can provide extensive mechanistic insight into telomere-associated gastric cancer progression and its use as a target in a variety of therapeutic interventions. In this study, we aimed to evaluate the clinical implications of c-Myc, human telomerase reverse transcriptase (hTERT) expression, and telomere length in patients with gastric cancer. A total of 57 gastric cancer cases and adjacent controls were included in the study. RT-PCR and immunohistochemistry were used to assess the expression levels of c-Myc and hTERT. The relative telomere length was measured by MMQPCR using the Cawthon method. Our results indicated that the shorter telomere and increased hTERT expression were associated with gastric cancer progression. The study also highlighted the role of short telomeres and increased expression of hTERT in gastric cancer progression and its association with various etiological risk factors, transcriptional activators, and overall survival among the ethnic Kashmiri population of North India.

TEAD4 nuclear localization and regulation by miR-4269 and miR-1343-3p in colorectal carcinoma.

BACKGROUND AND AIMS: TEAD4 transcription factor belonging to TEAD-family, is a key downstream element of the Hippo Signalling pathway and is very important for YAPinduced tumor progression. YAP-TEAD interaction is required to promote tumor progression and metastasis in various cancers. This study aims to investigate the role of TEAD4 in CRC progression and to compare the TEAD4 expression with different clinicopathological parameters of the study population. We also aim to explore the expression pattern of miR-4269 and miR-1343-3p and their functional role in TEAD4 mediated CRC progression. Furthermore, we intend to evaluate the prognostic significance of TEAD4, miR-4269, and miR-1343-3p in colorectal carcinoma. METHODS: Real-time PCR, Immunohistochemical Staining, and Western Blotting were performed on 71 human CRC tissue specimens and their adjacent normal tissues to evaluate the TEAD4 expression and the results were statistically analyzed against the clinicopathological variables of patient data and also with survival data using STATA software. miRNA expression was analyzed by quantitative real-time PCR. RESULTS: TEAD4 expression levels in tumor specimens were significantly higher than their paired normal specimens. The higher protein expression levels showed a significant association with TNM stage, Duke Stage, tumor grade, invasion depth, node status, necrosis of tumor tissue, lymphovascular and perineural invasion. As per the cox-regression model and classification tree analysis, TNM stage and perineural invasion were important predictors for TEAD4 expression and prognosis of CRC patients. Survival analysis indicated that TEAD4 overexpression was associated with poorer overall and disease-free survival. miR-4269 and miR-1343-3p were downregulated in CRC tumors and showed a negative correlation with TEAD4. The nuclear overexpressed TEAD4 and downregulated miR-4269 and miR-1343-3p evaluated for the first time in CRC, are believed to serve as important prognostic markers in CRC. CONCLUSION: Expression of TEAD4 was increased in CRC and was negatively regulated by miR-4269 and miR-1343-3p. The overexpression of TEAD4 is linked with poor overall and disease-free survival of CRC patients. These findings support prior observations and thus TEAD4 may be a possible prognostic marker in CRC.

Helicobacter pylori Subdues Cytokine Signaling to Alter Mucosal Inflammation via Hypermethylation of Suppressor of Cytokine Signaling 1 Gene During Gastric Carcinogenesis.

Helicobacter pylori infection has been associated with the onset of gastric mucosal inflammation and is known to perturb the balance between T-regulatory (Treg) and T-helper 17 (Th17) cells which causes a spurt of interleukin 17 (IL17) and transforming growth factor-ß (TGF-ß) from Th17 and Treg cells within the gastric milieu. IL17 instigates a surge of interleukin 6 (IL6) from T-helper 1 (Th1) and T-helper 2 (Th2) cells. Further, H. pylori infection is known to stimulate the atypical DNA methylation in gastric mucosa. However, the precise role of cytokine signaling in induction of epigenetic modifications during gastric carcinogenesis is vaguely understood. In this study, patient samples from were examined using real-time polymerase chain reaction (qPCR), PCR, methylation-specific (MS)-PCR, and enzyme-linked immunosorbent assays. We found that H. pylori infection augments the production of interleukin 10 (IL10), IL6, and TGF-ß in the gastric milieu and systemic circulation. Together with the IL6/IL10 mediated hyperactivation of the JAK/STAT pathway, H. pylori infection causes the inactivation of suppressor of cytokine signaling 1 (SOCS1) gene through the hypermethylation of the promoter region. This study signifies that H. pylori-mediated epigenetic silencing of SOCS1 in concert with inflammatory cytokines miffs hyperactivation of the JAK/STAT cascade during gastric carcinogenesis.

Nuclear localization and Overexpression of Smoothened in Pancreatic and Colorectal Cancers.

Smoothened (SMO) is a significant signalling protein which functions as a key transducer for the hedgehog signalling pathway, an important signalling mechanism with key roles in development and oncogenesis. The correlation of expression dynamics of SMO with pancreatic and colorectal cancer genesis has been known but with ambiguity. Therefore, in this study, we investigated messenger RNA (mRNA) and protein expression of SMO in pancreatic and colorectal cancers in our population and assessed relationship with various clinicopathological parameters. Surgically resected tumour and adjacent histologically normal tissues from 33 and 61 pancreatic and colorectal cancer patients were investigated in the present study. Expression of SMO was analysed by quantitative real-time polymerase chain reaction and immunohistochemistry. At mRNA level, SMO was overexpressed in 72.72% (24 of 33) and 50.81% (31 of 61) of the pancreatic and colorectal cancer cases as compared with their adjacent normal tissues. SMO immunohistochemical analysis revealed nuclear localization and overexpression was observed in 51.51% (17 of 33) and 40.98% (25 of 61) of pancreatic and colorectal cancer tissues. SMO overexpression was significantly associated with smoking, late-stage disease and lymph node metastasis in patients with Colorectal cancer. Our results showed that SMO is dysregulated in pancreatic and colorectal cancers and may be considered as a target in cancer therapeutics.

Pathological implications of Cx43 down-regulation in human colon cancer.

Connexin 43 is an important gap junction protein in vertebrates and is known for its tumor suppressive properties. Cx43 is abundantly expressed in the human intestinal epithelial cells and muscularis mucosae. To explore the role of Cx43 in the genesis of human colon cancer, we performed the expression analysis of Cx43 in 80 cases of histopathologically confirmed and clinically diagnosed human colon cancer samples and adjacent control tissue and assessed correlations with clinicopathological variables. Western blotting using anti-Cx43 antibody indicated that the expression of Cx43 was significantly down regulated (75%) in the cancer samples as compared to the adjacent control samples. Moreover, immunohistochemical analysis of the tissue samples confirmed the down regulation of the Cx43 in the intestinal epithelial cells. Cx43 down regulation showed significant association (p<0.05) with the histological type and tumor invasion properties of the cancer. Our data demonstrated that loss of Cx43 may be an important event in colon carcinogenesis and tumor progression, providing significant insights about the tumor suppressive properties of the Cx43 and its potential as a diagnostic marker for colon cancer.

Acute lymphoblastic leukemia presenting as a breast lump: A report of two cases.

Extra-medullary leukemic infiltration of the breast by acute lymphoblastic leukemia (ALL) is very rare. We report two cases of ALL presenting as breast masses and diagnosed on fine-needle aspiration (FNA). Our first patient, a post-partum 30-year-old female, developed bilateral breast lumps in her last trimester of pregnancy and complained of easy fatigability. Our second patient, a 14-year-old girl, presented with a right-breast lump of 1-week duration. She had received treatment for ALL 1 year back and had been in complete remission for the last 1 year. FNA of the breast nodules done in both the cases revealed diffuse infiltration by lymphoblasts. Subsequent hematological investigations confirmed bone marrow involvement by ALL in the first case and extra-medullary relapse in the second case. Fine-needle aspiration cytology (FNAC) is an easy and cost effective method for the early diagnosis of metastatic leukemic infiltration, avoiding unnecessary excisional biopsies in such cases.

Primary CNS lymphoma in immunocompetent: a review of literature and our experience from Kashmir.

AIM: To study the clinicopathological aspects of primary CNS lymphoma in immunocompetent patients. MATERIAL AND METHODS: Sixteen patients with primary CNS lymphoma were analyzed for their clinico-pathological characteristics and followed-up for the treatment and subsequent management in Neurosurgery, and Medical and Radiation Oncology. RESULTS: The fronto-parietal region was the commonest location of CNS lymphoma; four cases of cerebellar lymphoma were seen. Our patients were relatively young with a mean age of 48 years and an age range of 35-60 years. Females outnumbered males with a ratio of 2.7:1. The commonest presentation was focal neurological-deficits and features of raised intracranial pressure. All the patients histologically had diffuse large B-cell lymphoma. Radiologically, most presented as disc-enhancing lesions. Two patients had multiple lesions. Most of the patients (10) died within a mean of 4.4 months (range 2 weeks-16 months). CONCLUSION: Primary CNS lymphoma is seen in immunocompetent patients as well. Relapse is common after treatment and the overall prognosis is unfavorable.

Prepubertal testicular tumours in Kashmir--a histopathological report of 15 cases.

A total of 15 cases of prepubertal testicular tumours were reported by the department of pathology, Government Medical College, Srinagar, Kashmir over a period of 15 years, from January 1984 to December 1998. The cases included yolk sac tumour (10 cases; 67%), teratoma [(mature) 2 cases (13%)], rhabdomyosarcoma [(paratesticular) 2 cases (13%)] and NHL-Burkitt's lymphoma [one case (7%)]. The youngest patient was 10 months old and the oldest was of 14 years age. Ten cases (67%) occurred at or below the age of 4 years. The youngest patient had yolk sac tumour and oldest had rhabdomyosarcoma. In 2 cases both the testes were involved with one of these two cases having bilateral undescended testes.