Signaling Pathways
Advanced Transcriptomes Analysis
Several signaling pathways play crucial roles in the development and progression of cervical cancer. Dysregulation of these pathways often involves alterations in the expression or activity of multiple genes. Here are the key signaling pathways implicated in cervical cancer and examples of genes involved in each pathway:
Human Papillomavirus (HPV) Pathway
• HPV infection is a major risk factor for cervical cancer, with HPV oncoproteins (E6 and E7) playing central roles in carcinogenesis.
• Genes: HPV16 and HPV18 (high-risk types), E6 and E7 oncogenes, p53 (tumor suppressor protein), pRb (retinoblastoma protein).
Cell Cycle Regulation Pathway
• Dysregulation of cell cycle control mechanisms contributes to uncontrolled cell proliferation and tumor growth in cervical cancer.
• Genes: Cyclin D1 (CCND1), Cyclin E1 (CCNE1), Cyclin-dependent kinases (CDKs), Retinoblastoma protein (RB1), p21 (CDKN1A), p27 (CDKN1B).
Apoptosis Pathway
• Defects in apoptotic signaling pathways promote cell survival and resistance to cell death in cervical cancer cells.
• Genes: Bcl-2, Bcl-xL, Survivin (BIRC5), Caspases (e.g., Caspase-3, Caspase-8), TP53 (p53).
Wnt/β-Catenin Signaling Pathway
• Aberrant activation of the Wnt/β-catenin pathway is associated with cervical cancer initiation, progression, and metastasis.
• Genes: β-Catenin (CTNNB1), Wnt ligands (e.g., WNT5A, WNT7A), Axin (AXIN1), APC (Adenomatous Polyposis Coli), TCF/LEF transcription factors.
PI3K/Akt/mTOR Pathway
• Dysregulation of the PI3K/Akt/mTOR pathway promotes cell survival, proliferation, and angiogenesis in cervical cancer.
• Genes: Phosphatidylinositol 3-kinase (PI3K), Akt (Protein kinase B), mTOR (Mammalian Target of Rapamycin), PTEN (Phosphatase and Tensin Homolog), PDK1 (3-Phosphoinositide-dependent Protein Kinase-1).
Notch Signaling Pathway
• Notch signaling is involved in cervical cancer stemness, self-renewal, and tumor progression.
• Genes: Notch receptors (NOTCH1, NOTCH2, NOTCH3, NOTCH4), Notch ligands (e.g., Jagged1, Jagged2, Delta-like ligand 1), HES family transcription factors.
Epithelial-to-Mesenchymal Transition (EMT) Pathway
• Activation of EMT signaling promotes invasion, metastasis, and treatment resistance in cervical cancer.
• Genes: E-cadherin (CDH1), N-cadherin (CDH2), Vimentin (VIM), Snail (SNAI1), Slug (SNAI2), Twist (TWIST1).
Inflammatory Signaling Pathways
• Chronic inflammation contributes to cervical cancer development through the activation of pro-inflammatory signaling pathways.
• Genes: NF-κB (Nuclear Factor-kappa B), COX-2 (Cyclooxygenase-2), IL-6 (Interleukin-6), TNF-α (Tumor Necrosis Factor-alpha).
These pathways represent interconnected networks of signaling molecules and regulatory factors that coordinate cellular responses to extracellular cues and environmental stimuli. Dysregulation of these pathways contributes to the malignant transformation of cervical epithelial cells and the progression of cervical cancer.
Categorization of Possible Diagnoses
Negative (Normal) or NILM (Negative for Intraepithelial Lesion or Malignancy):
Serve as a baseline for comparison with other stages.This result indicates that no abnormal cells were found in the sample, and the cervical cells appear normal.
ASC-US (Atypical Squamous Cells of Undetermined Significance):
Reveal early molecular changes indicating the onset of dysplasia or precancerous lesions. This result suggests that some squamous cells appear abnormal, but the changes are not clearly precancerous. It is the most common abnormal finding in Pap smear results.
HPV Positive:
Provide insights into how HPV influences gene expression and pathway activation.This result indicates that the human papillomavirus (HPV) has been detected in the sample. Certain high-risk types of HPV can cause cervical cell changes that may lead to cancer if left untreated.
LSIL (Low-grade Squamous Intraepithelial Lesion):
Reveal progressive changes in gene expression and pathway activation as lesions become more severe. This result indicates mild abnormalities in the cervical cells, which are usually caused by HPV infection. In most cases, these changes resolve on their own without treatment.
HSIL (High-grade Squamous Intraepithelial Lesion):
Reveal progressive changes in gene expression and pathway activation as lesions become more severe. This result suggests more severe abnormalities in the cervical cells, which have a higher likelihood of progressing to cervical cancer if left untreated. Further testing and management are typically recommended.
ASC-H (Atypical Squamous Cells, cannot exclude HSIL):
This result indicates that some abnormal squamous cells are present, and the possibility of HSIL cannot be ruled out. Additional testing is usually needed to clarify the diagnosis.
AGC (Atypical Glandular Cells):
Provide insights into molecular changes specific to glandular cells in the cervix. This result suggests that some glandular cells appear abnormal. Glandular cells are found higher up in the cervical canal and are less common than squamous cell abnormalities. Further evaluation is usually necessary.
Squamous cell carcinoma or Adenocarcinoma:
Provide insights into molecular changes specific to glandular cells in the cervix. This result suggests that some glandular cells appear abnormal. Glandular cells are found higher up in the cervical canal and are less common than squamous cell abnormalities. Further evaluation is usually necessary.
EARLY DETECTION, PROGNOSIS, TREATMENT RESPONSE, AND THERAPEUTIC TARGETS
By performing transcriptome sequencing on samples representing each of eight conditions presented, we can gain a comprehensive understanding of the molecular changes that occur during cervical cancer development and progression.
This knowledge can lead to the identification of novel biomarkers for early detection, prognosis, and treatment response, as well as potential therapeutic targets.