Research

BACKGROUND: Bariatric surgery is an effective treatment for obesity. However, the degree of postoperative weight loss can vary greatly between patients, and the rationale behind such disparity remains unclear. Recent studies have suggested that genetics can influence the response to bariatric surgery, but little is known about the role of microRNAs (miRNAs) in this setting.

OBJECTIVES: To identify miRNA candidates that predict weight loss after bariatric surgery.

SETTING: Academic medical center.

METHODS: RNA was isolated from patients' blood collected at initial preoperative consult visits for bariatric surgery (laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy). Percentage of excess body mass index loss at 1-year follow-up was calculated to separate patients into 2 groups: high weight loss (HWL) and low weight loss (LWL). Twenty samples from each group were subjected to small RNA sequencing on an Illumina platform. Differential expression and downstream analyses were performed.

RESULTS: HWL and LWL groups had similar baseline demographics and makeup of operative procedures. In total, 5666 unique miRNAs were detected, of which only 3 exhibited significant differential expression: miR-1914-3p (P = 4.9 × 10-6), miR-664b-5p (P = 1.7 × 10-5), and miR-370-3p (P = 1.7 × 10-4). Downstream analyses revealed several potential genetic targets and enrichment for cellular metabolism and adipocyte differentiation pathways.

CONCLUSIONS: Small RNA sequencing revealed 3 candidate miRNAs with differential expression between weight loss groups that may be predictive of outcomes in patients after bariatric surgery. These findings contribute to the development of preoperative algorithms that further personalize obesity treatment decisions.

Background/Objectives: Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), also known as protein tyrosine phosphatase non-receptor type 6, functions as a tumor suppressor in breast, hepatocellular, and prostate cancers and an oncogene in glioblastoma and cervical cancer. A previous analysis of The Cancer Genome Atlas (TCGA) dataset revealed that lower SHP-1 transcript levels in bladder tumors were associated with poorer overall survival. Methods: This study aimed to evaluate the role of SHP-1 in bladder cancer and to assess the functional impact of its forced expression and knockdown in bladder carcinoma cell lines. SHP-1 expression was assessed in 19 bladder cancer cell lines and 26 bladder tissues. Lentiviral transduction was used to knock down or overexpress SHP-1 in four cell lines, followed by Western blot analysis of SHP-1 and pAkt/Akt protein expression. Results: SHP-1 protein levels were significantly lower in highly invasive cell lines (p < 0.001) and muscle-invasive tumors (p < 0.05). Functional studies demonstrated that SHP-1 modulation influenced the epithelial-mesenchymal transition (EMT) phenotype. SHP-1 expression was positively correlated with E-cadherin expression (p < 0.001) and negatively correlated with N-cadherin (p < 0.01) and Vimentin (p < 0.05) expression. Alteration of SHP-1 expression in bladder cancer cell lines affected proliferation, invasion, and migration (p < 0.05). RNA-seq analysis of the transduced cell lines revealed enrichment of gene sets related to EMT and signaling pathways involving MYC, PI3K, Akt, and mTOR. Furthermore, SHP-1 alteration impacted pAkt/Akt ratios (p < 0.05). Conclusions: Collectively, lower SHP-1 protein expression correlated with more aggressive phenotypes in bladder cancer cell lines and bladder tumors. In our limited dataset, reduced SHP-1 expression correlated with muscle-invasive disease, suggesting a potential link to more advanced tumor biology, consistent with TCGA associating reduced SHP-1 transcript expression to poorer survival rates. Our data provide preliminary functional evidence that SHP-1 may modulate Akt signaling in bladder cancer. Together, these results support further investigation of SHP-1 as a possible tumor suppressor, candidate prognostic biomarker, and potential therapeutic target in bladder cancer.

Microscopic vascular invasion (VI) predicts recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but cannot be accurately predicted before surgery. Thus, biomarkers that identify this aggressive tumor subset are needed. Here, we show that VI in stage I LUAD is associated with reproducible gene expression programs detectable beyond the invasive focus. Using bulk RNA sequencing of 162 resected tumors and spatial transcriptomics in a subset, we identify and characterize a VI-associated gene signature. A predictor derived from this signature is associated with VI and recurrence in an independent validation cohort and is robust to intra-tumor heterogeneity in multiregional sampling data. In a cohort of pre-surgical biopsies, predictor scores correlate with matched resections and show promising discrimination of VI. These findings indicate that VI-associated transcriptional changes extend across the tumor and are detectable in limited biopsy material, supporting further validation for preoperative risk stratification in stage I LUAD.

MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate protein expression. The human genome encodes more than 2,500 miRNAs, with each being able to modulate several targets, act along a variety of cellular pathways, and affect various tissues. They are frequently dysregulated in cancers and, via their protein targets, act as oncogenes or tumor-suppressors. As such, their effects are pervasive—miRNAs have been implicated in various biological processes including apoptosis, epithelial-to-mesenchymal transition, and angiogenesis. In this context, miRNA involved in metastasis have been termed “metastamiRs”. This chapter focuses on the role of miRNAs in the metastatic processes of prostate cancer. Our primary aims are to detail specific biological processes and molecular targets through which miRNAs act and that may serve as therapeutic targets. Secondly, we discuss the potential of miRNAs to serve as biomarkers of tumor aggression and thus potentially guide personalized therapy.

Bladder cancer is among the most common cancers globally, with significant mortality associated with more advanced disease. Early detection and diagnostic accuracy are thus fundamental to the clinical pathway for managing bladder cancer. MicroRNA (miRNA) are small, non-coding segments of RNA that regulate gene expression and have been implicated in the process of carcinogenesis. Dysregulation and aberrant expression of miRNAs have been shown to have both oncogenic and tumor suppressive effects. A vast number of miRNA, across the entire field of cancer biology, have already been identified and characterized, and many of these have been associated with bladder cancer. These miRNAs have furthered our understanding of the genetic profile of bladder cancer, and ultimately, may be utilized in the detection, prognosis, and treatment of this disease. This chapter focuses on the role of miRNA in the pathogenesis of metastatic bladder cancer and overviews many of the miRNA thought to be associated with bladder cancer.  Additionally, this chapter explores the clinical utilities of miRNAs in bladder cancer to serve as biomarkers and guide individualized treatment.

MicroRNAs are short noncoding RNAs that regulate post-transcriptional protein expression. Aberrant microRNA expression has been widely implicated in cancer biology with various effects depending on the affected downstream target(s). In renal cell carcinoma, microRNAs have been shown to influence metastasis by targeting oncogenes or tumor suppressors in complex regulatory networks­­ - leading them to be coined “metastamiRs.” This chapter aims to identify the microRNAs responsible for metastasis in renal cell carcinoma, review their molecular function and oncologic outcome, and discuss their potential roles for diagnosis, prognosis, and therapy.