non coding RNA alterations

Question 1

1. Define non-coding RNAs and describe the main classes of non-coding RNAs.

Answer 1

Answer

Non-coding RNAs (ncRNAs) are RNA molecules that do not encode proteins but still perform key regulatory and structural functions in the cell. They can range from short RNAs (e.g., microRNAs) to long non-coding RNAs (>200 nt).
Major classes include:

Small RNAs (<200 nt) such as microRNAs (miRNAs), which regulate gene expression at the post-transcriptional level.

Long non-coding RNAs (lncRNAs) (>200 nt), which can modulate chromatin structure, transcription, RNA splicing, translation, or act as scaffolds.

Circular RNAs (circRNAs), which form covalently closed loops and regulate transcription, RNA splicing, translation, and often act as miRNA sponges.

Lecture 6- Non-coding RNA alter…

Question 2

2. Describe the canonical mechanism by which microRNAs regulate gene expression.

Answer 2

Answer

In the canonical pathway, mature miRNAs are incorporated into the RNA-induced silencing complex (RISC). The miRNA then binds partially complementary sequences in the 3′ untranslated region (3′UTR) of target mRNAs, causing:

mRNA cleavage

Translational repression

mRNA deadenylation, resulting in decreased stability

This allows miRNAs to fine-tune gene expression post-transcriptionally.

Lecture 6- Non-coding RNA alter…

Question 3

3. Explain how miRNAs can act as oncogenes and tumour suppressors, and provide one example of each.

Answer 3

Answer

Onco-miRs: miRNAs that promote cancer by inhibiting tumour suppressor genes.
Example: Overexpressed miRNAs in cancer may suppress genes preventing proliferation or metastasis.

Tumour-suppressive miRs: miRNAs that suppress cancer by targeting oncogenes.
Example: Loss of these miRNAs results in unchecked oncogene expression.

Lecture 6- Non-coding RNA alter…

Question 4

4. Describe how the miR-200 family regulates EMT and metastasis.

Answer 4

Answer

The miR-200 family (miR-200a/b/c, miR-141, miR-429) targets the transcription factors ZEB1 and ZEB2, which normally repress E-cadherin.

High miR-200 levels: inhibit ZEB1/2 → increase E-cadherin → maintain epithelial phenotype → reduced EMT and metastasis

Low miR-200 levels: ZEB1/2 rise → repress E-cadherin → promote mesenchymal phenotype → enhanced EMT and metastasis

Lecture 6- Non-coding RNA alter…

Question 5

5. Explain how miR-200b regulates angiogenesis in cancer.

Answer 5

Answer

miR-200b normally targets QKI, a protein essential for blood vessel formation.
In cancers such as lung cancer:

miR-200b levels decrease, leading to increased QKI expression

High QKI promotes angiogenesis, supporting tumour growth and metastatic spread

Lecture 6- Non-coding RNA alter…

Question 6

6. What are circRNAs, how are they formed, and what are their major functions?

Answer 6

Answer

Circular RNAs (circRNAs) are single-stranded RNA molecules forming a covalently closed loop, generated by back-splicing of mRNA precursors.
Their functions include:

Transcriptional regulation by interacting with transcription machinery

Splicing regulation by competing with linear mRNA splicing

Post-transcriptional regulation, often acting as miRNA sponges

Translational control by binding translation initiation factors

Some circRNAs may even be translated themselves

Lecture 6- Non-coding RNA alter…

Question 7

7. Describe the mechanism by which circRNA-10720 promotes metastasis in hepatocellular carcinoma.

Answer 7

Answer

In hepatocellular carcinoma:

Twist1, a transcription factor that represses E-cadherin to promote EMT, upregulates circRNA-10720.

circRNA-10720 sponges miRNAs that normally target vimentin.

Vimentin expression therefore increases.

Elevated vimentin promotes the mesenchymal phenotype, enhancing metastasis.

Thus, circRNA-10720 contributes to EMT and metastasis by releasing vimentin from miRNA repression.

Lecture 6- Non-coding RNA alter…

Question 8

8. Explain how circ-MAPK4 contributes to apoptosis evasion in glioma.

Answer 8

Answer

In glioma cells:

circ-MAPK4 is overexpressed and functions as a miR-125a sponge.

miR-125a normally activates the p38 MAPK pathway, which triggers apoptosis in response to stress or DNA damage.

By sponging miR-125a, circ-MAPK4 reduces p38 MAPK activation, enabling tumour cells to evade apoptosis.

Lecture 6- Non-coding RNA alter…

Question 9

9. Outline the major regulatory functions of lncRNAs and explain how these can contribute to cancer.

Answer 9

Answer

lncRNAs (>200 nt) regulate gene expression through:

Chromatin remodelling

Transcription activation or repression

Modulation of RNA splicing

Scaffolding protein complexes

Protein localisation and transport

Translational regulation

miRNA sponging

Serving as precursors for small RNAs

Alterations in lncRNA expression can lead to abnormal activation/silencing of pathways controlling proliferation, apoptosis, invasion, and metastasis—driving numerous hallmarks of cancer.

Lecture 6- Non-coding RNA alter…

Question 10

10. Discuss how MALAT1 contributes to cancer progression and metastasis.

Answer 10

Answer

MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1):

Sponges miR-200c, reducing its ability to inhibit EMT; this promotes a mesenchymal, metastatic phenotype.

Recruits PRC2 to repress genes like E-cadherin, enhancing EMT and metastasis.

Interestingly, in some contexts it binds and inactivates TEADs, suppressing pro-metastatic gene expression (showing context-dependent roles).

Overall, MALAT1 participates in metastasis through multiple mechanisms involving EMT regulation and chromatin modification.

Lecture 6- Non-coding RNA alter…

Question 11

11. Describe the role of HOTAIR in cancer.

Answer 11

Answer

HOTAIR (HOX Transcript Antisense Intergenic RNA):

Recruits chromatin-remodelling complexes such as PRC, leading to gene silencing that promotes tumour progression.

Sponges miRNAs and modulates transcription factors affecting cancer-relevant genes.

Strongly associated with breast cancer metastasis and poor patient survival, as well as involvement in many other cancers.

Lecture 6- Non-coding RNA alter…

Question 12

12. Identify cancer-related physiological processes affected by non-coding RNA dysregulation. Provide examples.

Answer 12

Answer

ncRNA alterations affect many cancer hallmarks, including:

1. Metastasis / EMT

miR-200 family loss → increased ZEB1/2 → EMT

MALAT1 sponging miR-200c → promotes EMT

circRNA-10720 → ↑ vimentin → mesenchymal state

2. Angiogenesis

Reduced miR-200b → ↑ QKI → enhanced angiogenesis

3. Apoptosis evasion

circ-MAPK4 sponges miR-125a → ↓ p38 MAPK-mediated apoptosis

4. Proliferation

lncRNAs such as HOTAIR modulate chromatin to activate proliferation pathways

These dysregulations enable tumour survival, invasion, and growth.

Question 13

1. Which statement correctly describes long non-coding RNAs (lncRNAs)?

A. All lncRNAs are translated into proteins
B. lncRNAs function only in the cytoplasm
C. lncRNAs can regulate chromatin remodelling, transcription, and RNA splicing
D. lncRNAs are always less than 200 nucleotides

Answer 13

Correct answer: C

Lecture 6- Non-coding RNA alter…

Question 14

2. Which type of ncRNA is primarily generated by “back-splicing”?

A. miRNA
B. snoRNA
C. lncRNA
D. circRNA

Answer 14

Correct answer: D

Lecture 6- Non-coding RNA alter…

Question 15

3. Which statement best describes an onco-miR?

A. A miRNA that inhibits cell division
B. A miRNA that targets tumour suppressor genes
C. A mutated miRNA that produces a protein
D. A miRNA that activates apoptosis

Answer 15

Correct answer: B

Lecture 6- Non-coding RNA alter…

Question 16

4. Which non-coding RNA alteration promotes metastasis by sponging miRNAs that normally target vimentin?

A. circ-MAPK4
B. miR-200 family
C. circRNA-10720
D. MALAT1

Answer 16

Correct answer: C

Lecture 6- Non-coding RNA alter…

Question 17

5. Which non-coding RNA alteration promotes apoptosis evasion in glioma?

A. HOTAIR silencing
B. Loss of miR-200b
C. circ-MAPK4 overexpression
D. Increased miR-125a

Answer 17

Correct answer: C

Question 18

6. Define microRNA (miRNA). (2 marks)

Answer 18

Small 18–25 nt non-coding RNAs that regulate gene expression post-transcriptionally through RISC-mediated mRNA degradation or translational repression.

Lecture 6- Non-coding RNA alter…

Question 19

7. Name two cancer-related processes affected by non-coding RNA alterations. (2 marks)

Answer 19

Metastasis, angiogenesis, apoptosis evasion, proliferation. (Any two)

Lecture 6- Non-coding RNA alter…

Question 20

8. What is the canonical function of a mature miRNA? (2 marks)

Answer 20

Bind partially complementary sequences in the 3′UTR of target mRNA to trigger mRNA degradation or translational repression.

Lecture 6- Non-coding RNA alter…

Question 21

9. Name the two major ncRNAs involved in sponging miRNAs. (2 marks)

Answer 21

circRNAs and lncRNAs.

Lecture 6- Non-coding RNA alter…

Question 22

10. What is the role of ZEB1/2 in EMT? (2 marks)

Answer 22

ZEB1/2 repress E-cadherin transcription to promote EMT.

Lecture 6- Non-coding RNA alter…

Question 23

11. How does MALAT1 promote EMT? (4 marks)

Answer 23

MALAT1 sponges miR-200c, reducing miR-200c levels and releasing ZEB1/2 from repression. This decreases E-cadherin and promotes EMT.

Lecture 6- Non-coding RNA alter…

Question 24

12. How can circRNAs regulate translation? (4 marks)

Answer 24

They bind translation-related proteins (eIF4G, PABP) to suppress translation or compete with linear mRNAs for ribosome access (“mRNA traps”).

Lecture 6- Non-coding RNA alter…

Question 25

13. Explain how miRNA deregulation contributes to cancer development. (4 marks)

Answer 25

Onco-miRs suppress tumour suppressor genes, while tumour-suppressive miRNAs target oncogenes. Alterations in their levels disrupt gene expression and promote cancer progression. Lecture 6- Non-coding RNA alter…

Question 26

14. What is vimentin and why is its expression important in metastasis? (2 marks)

Answer 26

A cytoskeletal filament protein essential for the mesenchymal phenotype; high vimentin promotes cell migration and metastasis. Lecture 6- Non-coding RNA alter…

Question 27

15. How does reduced miR-200b expression enhance tumour angiogenesis? (4 marks)

Answer 27

Lower miR-200b allows increased QKI expression. QKI promotes blood vessel formation, supporting tumour angiogenesis.

Question 28

18. Explain how non-coding RNA alterations influence multiple cancer hallmarks. (6 marks)

Answer 28

miRNA loss can increase oncogene expression; onco-miRs can suppress tumour suppressors; circRNAs can sponge tumour-suppressive miRNAs; lncRNAs can recruit chromatin-remodelling complexes to silence anti-metastatic genes. These alterations affect proliferation, angiogenesis, EMT, invasion, and apoptosis evasion. Lecture 6- Non-coding RNA alter…

Question 29

19. Describe two ways circRNAs modify gene expression relevant to cancer progression. (4 marks)

Answer 29

Act as miRNA sponges to release oncogenic targets from repression; compete with linear mRNA splicing to alter gene isoforms; regulate transcription by interacting with transcription complexes; inhibit translation by binding initiation factors. (Any two) Lecture 6- Non-coding RNA alter…

Question 30

20. Why is dysregulation of miRNA biogenesis itself a cancer-promoting mechanism? (4 marks)

Answer 30

Disruption of miRNA maturation reduces levels of tumour-suppressive miRNAs and can increase levels of onco-miRs, leading to widespread mis-regulation of cancer-associated genes.